Polymers containing poly(hydroxyalkanoates) and agents for use with medical articles and methods of fabricating the same

ABSTRACT

Polymers containing poly(hydroxyalkanoates) and agents for use with medical articles and methods of fabricating the same are disclosed. The medical article generally comprises an implantable substrate having a coating, and the coating contains a poly(hydroxyalkanoate).

BACKGROUND

1. Field of the Invention

This invention is directed to polymers for use with medical articlesand, more specifically, polymers containing poly(hydroxyalkanoates) andagents.

2. Description of the State of the Art

A current paradigm in biomaterials research is the control of proteinadsorption on an implant surface. Uncontrolled protein adsorption on animplant surface is a problem with current biomaterial implants and leadsto a mixed layer of partially denatured proteins on the implant surface.This mixed layer of partially denatured proteins leads to disease, forexample, by providing cell-binding sites from adsorbed plasma proteinssuch as fibrinogen and immunoglobulin G. Platelets and inflammatorycells such as, for example, monocytes, macrophages and neutrophils,adhere to the cell-binding sites. A wide variety of proinflammatory andproliferative factors may be secreted and result in a diseased state.Accordingly, a non-fouling surface, which is a surface that does notbecome fouled or becomes less fouled with this layer of partiallydenatured proteins, is desirable.

A stent is an example of an implant that can benefit from a non-foulingsurface. Stents are a mechanical intervention that can be used as avehicle for delivering pharmaceutically active agents. As a mechanicalintervention, stents can physically hold open and, if desired, expand apassageway within a subject. Typically, a stent may be compressed,inserted into a small vessel through a catheter, and then expanded to alarger diameter once placed in a proper location. Examples of patentsdisclosing stents include U.S. Pat. Nos. 4,733,665, 4,800,882 and4,886,062.

Stents play an important role in a variety of medical procedures suchas, for example, percutaneous transluminal coronary angioplasty (PTCA),which is a procedure used to treat heart disease. In PTCA, a ballooncatheter is inserted through a brachial or femoral artery, positionedacross a coronary artery occlusion, inflated to compress atheroscleroticplaque and open the lumen of the coronary artery, deflated andwithdrawn. Problems with PTCA include formation of intimal flaps or tornarterial linings, both of which can create another occlusion in thelumen of the coronary artery. Moreover, thrombosis and restenosis mayoccur several months after the procedure and create a need foradditional angioplasty or a surgical by-pass operation. Stents aregenerally implanted to reduce occlusions, inhibit thrombosis andrestenosis, and maintain patency within vascular lumens such as, forexample, the lumen of a coronary artery.

Local delivery of agents is often preferred over systemic delivery ofagents, particularly where high systemic doses are necessary to achievean effect at a particular site within a subject, because high systemicdoses of agents can often create adverse effects within the subject. Oneproposed method of local delivery includes coating the surface of amedical article with a polymeric carrier and attaching an agent to, orblending it with, the polymeric carrier. Some of the currently desiredpolymeric materials such as, for example, the poly(hydroxyalkanoates)are biodegradable. Unfortunately, these polymers do not have sufficientmechanical properties for a number of medical applications. For example,the mechanical properties of currently available poly(hydroxyalkanoates)have been found to be insufficient for many stent applications.Accordingly, there is a need for poly(hydroxyalkanoates) with improvedmechanical properties.

Another set of problems are associated with the release of agents frombiodegradable coatings within a subject. One problem is that the releaserate and absorption rate of biodegradable coatings should becontrollable. The absorption rate of currently availablepoly(hydroxyalkanoates), for example, is too slow for most applications.Another problem involves regulatory concerns in that molecules from apolymeric carrier may remain attached to an agent upon breakdown of thecoating. Since these additional molecules were not considered in theoriginal regulatory approval of the agent, there may be regulatoryconcerns over possible changes in the agent's biological activity.

Accordingly, there is a need for poly(hydroxyalkanoate) coatings (i)that have sufficient mechanical properties for applications that canbenefit from biodegradable polymers, (ii) that can release agents thatare substantially free of additional molecules derived from a polymericcarrier, (iii) that can be designed to have a predetermined release rateand absorption rate; and (iv) that can be combined with agents that arenot only bioactive and/or biobeneficial but also control a physicalproperty and/or a mechanical property of a medical article formed fromthe polymer.

SUMMARY

Embodiments of the present invention generally encompass polymerscontaining poly(hydroxyalkanoates) and agents such as diagnostic,prophylactic, therapeutic, ameliorative, and other agents, for use withmedical articles. The polymers can be used in medical articles such as,for example, stents, as well as coatings for such medical articles.Methods for fabricating the polymers are also disclosed.

In some embodiments, the invention can include a polymer represented bythe following formula:

wherein the ratio of A:B may be less than, greater than, or equal toone, and A comprises

at least one of L₁, B, L₂ or X comprises an agent that is bioactiveand/or biobeneficial, wherein the agent also affects a physical propertyand/or a mechanical property of a composition comprising the polymer;each R₁ is independently selected from a group consisting of alkylenes,alkanoates, alkyl alkanoates, diesters, acylals, diacids, saturatedfatty acids, glycerides, and combinations thereof, provided that thereis at least one hydroxyalkanoate moiety within the polymer after theselection of R₁; and, provided that the at least one hydroxyalkanoatemoiety is present in the polymer in an amount sufficient to produce apolymer with a behavior that is characteristic of apoly(hydroxyalkanoate); R₂ through R₄ are independently selected from agroup consisting of hydrogen; substituted, unsubstituted, hetero-,straight-chained, branched, cyclic, saturated and unsaturated aliphaticradicals; and substituted, unsubstituted, and hetero-aromatic radicals;L₁ is an optional linkage connecting the A moiety to the B moiety; X isan optional agent; L₂ is an optional linkage connecting X to thepolymer; k and m are independently selected integers; and n and z areintegers not equal to zero. In these or other embodiments, the polymercan be biodegradable and can also contain an additional agent that isblended, mixed, bonded, or otherwise combined with the polymer.

In other embodiments, the invention also provides a compositioncomprising a blend or mixture of (i) a polymer comprising apoly(hydroxyalkanoate) and (ii) an agent, wherein the agent is bioactiveand/or biobeneficial and also controls a physical property and/or amechanical property of a medical article formed from the blend ormixture.

In other embodiments, the invention also provides poly(hydroxyalkanoate)coatings and medical articles that include an agent with properties thatmay be biobeneficial, bioactive, diagnostic or have a combination ofthese characteristics. In other embodiments, the medical article mayinclude a stent that provides for local delivery of an agent. In otherembodiments, the methods comprising fabricating the polymers, medicalarticles and/or coatings optionally include annealing.

DETAILED DESCRIPTION

As discussed in more detail below, embodiments of the present inventiongenerally encompass compositions including a poly(hydroxyalkanoate)(PHA) and an agent such as, for example, a therapeutic, prophylactic,diagnostic and/or other agent, for use with medical articles. Theinvention also encompasses methods for fabricating the compositions. Themedical articles comprise any medical device such as, for example, animplantable medical device such as a stent. In some embodiments, thecompositions can be used as a coating on the implantable substrate. Inother embodiments, a medical device such as a stent is made in whole orin part from the composition.

An “agent” can be a moiety that may be bioactive, biobeneficial,diagnostic, plasticizing, or have a combination of thesecharacteristics. A “moiety” can be a functional group composed of atleast 1 atom, a bonded residue in a macromolecule, an individual unit ina copolymer or an entire polymeric block. It is to be appreciated thatany medical articles that can be improved through the teachingsdescribed herein are within the scope of the present invention. Examplesof medical devices include, but are not limited to, stents,stent-grafts, vascular grafts, artificial heart valves, foramen ovaleclosure devices, cerebrospinal fluid shunts, pacemaker electrodes,guidewires, ventricular assist devices, cardiopulmonary bypass circuits,blood oxygenators, coronary shunts (AXIUS™, Guidant Corp.) andendocardial leads (FINELINE® and ENDOTAK®, Guidant Corp.).

The medical devices can be comprised of a metal or an alloy, including,but not limited to, ELASTINITE® (Guidant Corp.), NITINOL® (NitinolDevices and Components), stainless steel, tantalum, tantalum-basedalloys, nickel-titanium alloy, platinum, platinum-based alloys such as,for example, platinum-iridium alloys, iridium, gold, magnesium,titanium, titanium-based alloys, zirconium-based alloys, alloyscomprising cobalt and chromium (ELGILOY®, Elgiloy Specialty Metals,Inc.; MP35N and MP20N, SPS Technologies) or combinations thereof. Thetradenames “MP35N” and “MP20N” describe alloys of cobalt, nickel,chromium and molybdenum. The MP35N consists of 35% cobalt, 35% nickel,20% chromium, and 10% molybdenum. The MP20N consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Medical devices withstructural components that are comprised of bioabsorbable polymers orbiostable polymers are also included within the scope of the presentinvention.

The Polymeric Compositions

The PHA compositions of the present invention include any combination ofpolymers, copolymers and agents, wherein the combination comprises ahydroxyalkanoate moiety. Polymers comprising hydroxyalkanoate moietiescan be biodegradable due to the labile nature of the ester groups thatcan be present between at least the hydroxyalkanoate moieties.Accordingly, these compositions can be designed such that they can bebroken down, absorbed, resorbed and eliminated by a mammal. Thecompositions of the present invention can be used, for example, to formmedical articles and coatings.

The terms “combine,” “combined,” and “combining” all refer to arelationship between components of a composition and include blends,mixtures, linkages, and combinations thereof, of components that formthe compositions. The linkages can be connections that are physical,chemical, or a combination thereof. Examples of physical connectionsinclude, but are not limited to, an interlinking of components that canoccur, for example, in interpenetrating networks and chain entanglement.Examples of chemical connections include, but are not limited to,covalent and non-covalent bonds. Covalent bonds include, but are notlimited to, simple covalent bonds and coordinate bonds. Non-covalentbonds include, but are not limited to, ionic bonds, and inter-molecularattractions such as, for example, hydrogen bonds and attractions createdby induced and permanent dipole-dipole interactions.

Compositions that are selected for an in vivo use should meet particularrequirements with regard to physical, mechanical, chemical, andbiological properties of the compositions. An example of a physicalproperty that can affect the performance of a biodegradable compositionin vivo is water uptake. An example of a mechanical property that canaffect the performance of a composition in vivo is the ability of thecomposition to withstand stresses that can cause mechanical failure ofthe composition such as, for example, cracking, flaking, peeling, andfracturing. An example of a chemical property that can affectperformance of a biodegradable composition in vivo is the rate ofabsorption of the composition by a subject. An example of a biologicalproperty that can affect performance of a composition in vivo is thebioactive and/or biobeneficial nature of the composition, both of whichare described below.

While not intending to be bound by any theory or mechanism of action,water uptake by a composition can be an important characteristic in thedesign of a composition. Water can act as a plasticizer for modifyingthe mechanical properties of the composition. Control of water uptakecan also provide some control over the hydrolysis of a coating and thuscan provide control over the degradation rate, absorption rate, and theagent release rate of a medical article or coating in vivo. In someembodiments, an increase in hydrolysis can also increase the releaserate of an agent by creating channels within a medical article orcoating that can serve as transport pathways for diffusion of the agentsfrom the composition. The terms “subject” and “patient” can be usedinterchangeably and refer to an animal such as a mammal including, butnot limited to, non-primates such as, for example, a cow, pig, horse,cat, dog, rat, and mouse; and primates such as, for example, a monkey ora human.

The compositions of the present invention can be used to form medicalarticles and coatings (i) that have sufficient mechanical properties forapplications that can benefit from biodegradable polymers, (ii) that canrelease agents substantially free of additional molecules derived from apolymeric carrier, (iii) that can be designed to have a predeterminedrelease rate and absorption rate; and (iv) that can be combined withagents that are not only bioactive and/or biobeneficial but also controla physical property and/or a mechanical property of a medical article orcoating formed from the polymer.

For the purposes of the present invention, a polymer or coating is“biodegradable” when it is capable of being completely or substantiallydegraded or eroded when exposed to an in vivo environment or arepresentative in vitro. A polymer or coating is capable of beingdegraded or eroded when it can be gradually broken-down, resorbed,absorbed and/or eliminated by, for example, hydrolysis, enzymolysis,oxidation, metabolic processes, bulk or surface erosion, and the likewithin a subject. It should be appreciated that traces or residue ofpolymer may remain on the device, near the site of the device, or nearthe site of a biodegradable device, following biodegradation. The terms“bioabsorbable” and “biodegradable” are used interchangeably in thisapplication. The polymers used in the present invention may bebiodegradable and may include, but are not limited to, condensationcopolymers.

A PHA composition of the present invention comprises at least onehydroxyalkanoate monomer, wherein the at least one hydroxyalkanoatemoiety is present in the polymer in an amount sufficient to produce apolymer with a behavior that is characteristic of apoly(hydroxyalkanoate). The PHAs can also contain a wide variety ofother moieties and, as a result, can have a wide variety of molecularconfigurations. The chemical structure of the PHA compositions isdiscussed below.

Poly(hydroxyalkanoates) can be obtained from a biological source or froma chemical synthesis. The biological source can be a microorganism, ahigher organism such as a plant or a genetically modified bioreactorsuch as a host cell that can be a prokaryote or a eukaryote. Methodsused to produce PHAs biologically are known in the art such as, forexample, those methods discussed in U.S. Pat. Nos. 4,910,145; 5,245,023;5,250,430; 5,480,794; 5,512,669; and 5,534,432. Methods of producingPHAs through chemical synthesis include, but are not limited to,ring-opening polymerization of β-lactone monomers and condensationpolymerization of esters of 3-hydroxy alkanioc acids, each of which arediscussed in U.S. Pat. Nos. 6,610,764 and 5,563,239, respectively.

In some embodiments, the PHA compositions can comprise other polymersthat can be combined with the PHA to form a PHA composition. In someembodiments, polymers other than PHA can be crosslinked with the PHAusing, for example, an isocyanate, a diisocyanate, diacyl halide, diene,or another crosslinking agent discussed herein or known to one of skillin the art.

The amount of the polymers other than PHA that are combined with a PHAshould be limited by the effect that the other polymers have on adesired performance parameter of a product formed from the composition.Such performance parameters may include, for example, the toughness of amedical device or coating, the capacity for the loading concentration ofan agent, and the rate of biodegradation and elimination of thecomposition from a subject. If the other polymers in a composition arenon-biodegradable, they should be sized to produce polymer fragmentsthat can clear from the subject following biodegradation of thecomposition.

In some embodiments, the number average molecular weight of the polymerfragments should be at or below about 40,000 Daltons, or any rangetherein. In other embodiments, the molecular weight of the fragmentsrange from about 300 Daltons to about 40,000 Daltons, from about 8,000Daltons to about 30,000 Daltons, from about 10,000 Daltons to about20,000 Daltons, or any range therein. The molecular weights are taughtherein as a number average molecular weight.

Examples of other polymers that can be combined with the PHAs of thepresent invention include, but are not limited to, poly(acrylates) suchas poly(butyl methacrylate), poly(ethyl methacrylate), poly(hydroxylethyl methacrylate), poly(ethyl methacrylate-co-butyl methacrylate),copolymers of ethylene-methyl methacrylate;poly(2-acrylamido-2-methylpropane sulfonic acid), and polymers andcopolymers of aminopropyl methacrylamide; poly(cyanoacrylates);poly(carboxylic acids); poly(vinyl alcohols); poly(maleic anhydride) andcopolymers of maleic anhydride; fluorinated polymers or copolymers suchas poly(vinylidene fluoride), poly(vinylidene fluoride-co-hexafluoropropene), poly(tetrafluoroethylene), and expandedpoly(tetrafluoroethylene); poly(sulfone); poly(N-vinyl pyrrolidone);poly(aminocarbonates); poly(iminocarbonates); poly(anhydride-co-imides),poly(hydroxyvalerate); poly(L-lactic acid); poly(L-lactide);poly(caprolactones); poly(lactide-co-glycolide); poly(hydroxybutyrates);poly(hydroxybutyrate-co-valerate); poly(dioxanones); poly(orthoesters);poly(anhydrides); poly(glycolic acid); poly(glycolide); poly(D,L-lacticacid); poly(D,L-lactide); poly(glycolic acid-co-trimethylene carbonate);poly(phosphoesters); poly(phosphoester urethane); poly(trimethylenecarbonate); poly(iminocarbonate); poly(ethylene); poly(propylene)co-poly(ether-esters) such as, for example, poly(dioxanone) andpoly(ethylene oxide)/poly(lactic acid); poly(anhydrides), poly(alkyleneoxalates); poly(phosphazenes); poly(urethanes); silicones; poly(esters;poly(olefins); copolymers of poly(isobutylene); copolymers ofethylene-alphaolefin; vinyl halide polymers and copolymers such aspoly(vinyl chloride); poly(vinyl ethers) such as poly(vinyl methylether); poly(vinylidene halides) such as, for example, poly(vinylidenechloride); poly(acrylonitrile); poly(vinyl ketones); poly(vinylaromatics) such as poly(styrene); poly(vinyl esters) such as poly(vinylacetate); copolymers of vinyl monomers and olefins such aspoly(ethylene-co-vinyl alcohol) (EVAL), copolymers ofacrylonitrile-styrene, ABS resins, and copolymers of ethylene-vinylacetate; poly(amides) such as Nylon 66 and poly(caprolactam); alkydresins; poly(carbonates); poly(oxymethylenes); poly(imides); poly(esteramides); poly(ethers) including poly(alkylene glycols) such as, forexample, poly(ethylene glycol) and poly(propylene glycol); epoxy resins;polyurethanes; rayon; rayon-triacetate; biomolecules such as, forexample, fibrin, fibrinogen, starch, poly(amino acids); peptides,proteins, gelatin, chondroitin sulfate, dermatan sulfate (a copolymer ofD-glucuronic acid or L-iduronic acid and N-acetyl-D-galactosamine),collagen, hyaluronic acid, and glycosaminoglycans; other polysaccharidessuch as, for example, poly(N-acetylglucosamine), chitin, chitosan,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, and carboxymethylcellulose; and derivatives, analogs,homologues, congeners, salts, copolymers and combinations thereof. Insome embodiments, the other polymers are selected such that theyspecifically exclude any one or any combination of these polymers.

In some embodiments, the other polymers can be biodegradable. Examplesof biodegradable polymers include, but are not limited to, polymershaving repeating units such as, for example, an α-hydroxycarboxylicacid, a cyclic diester of an α-hydroxycarboxylic acid, a dioxanone, alactone, a cyclic carbonate, a cyclic oxalate, an epoxide, a glycol, ananhydride, a lactic acid, a glycolic acid, a lactide, a glycolide, anethylene oxide, an ethylene glycol, or combinations thereof. In otherembodiments, the biodegradable polymers include, but are not limited to,polyesters, poly(ester amides); amino acids; PEG and/or alcohol groups,polycaprolactones, poly(L-lactide), poly(D,L-lactide),poly(D,L-lactide-co-PEG) block copolymers,poly(D,L-lactide-co-trimethylene carbonate), polyglycolides,poly(lactide-co-glycolide), polydioxanones, polyorthoesters,polyanhydrides, poly(glycolic acid-co-trimethylene carbonate),polyphosphoesters, polyphosphoester urethanes, poly(amino acids),polycyanoacrylates, poly(trimethylene carbonate), poly(imino carbonate),polycarbonates, polyurethanes, copoly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, PHA-PEG, and any derivatives,analogs, homologues, salts, copolymers and combinations thereof. Inother embodiments, the other polymers can be poly(glycerol sebacate);tyrosine-derived polycarbonates containing desaminotyrosyl-tyrosinealkyl esters such as, for example, desaminotyrosyl-tyrosine ethyl ester(poly(DTE carbonate)); and any derivatives, analogs, homologues, salts,copolymers and combinations thereof. In some embodiments, the otherpolymers are selected such that they specifically exclude any one or anycombination of these polymers.

In some embodiments, the other polymers can be chemically connected to aPHA by covalent bonds. In other embodiments, the other polymers can bechemically connected to a PHA by non-covalent bonds such as, forexample, by ionic bonds, inter-molecular attractions, or a combinationthereof. In other embodiments, the other polymers can be physicallyconnected to a PHA. In other embodiments, the other polymers can bechemically and physically connected with a PHA. Examples of ionicbonding can include, but are not limited to, ionic bonding of an anionicsite to a cationic site between polymers. In some embodiments, ananionic site can be bound to a quaternary amine. Examples ofinter-molecular attractions include, but are not limited to, hydrogenbonding such as, for example, the permanent dipole interactions betweenhydroxyl, amino, carboxyl, amide, and sulfhydryl groups, andcombinations thereof. Examples of physical connections can include, butare not limited to, interpenetrating networks and chain entanglement.The polymers can also be blended or mixed with the PHAs.

With respect to the chemical notation used herein, each of thefunctional groups R may or may not be numbered for clarity in aparticular teaching and can be independently selected from any group,subgroup, or combination thereof, as specified herein. These groups,subgroups, and combinations thereof, can include H; substituted,unsubstituted, hetero-, straight-chained, branched, cyclic, saturated orunsaturated aliphatic radicals; substituted, unsubstituted, orhetero-aromatic radicals; or a combination thereof. For example, an Rgroup can be a H; an aliphatic hydrocarbon group such as, for example,an alkyl, alkenyl, or alkynyl group; an aromatic group such as, forexample, an aryl, aralkyl, aralkenyl, of aralkynyl group; various othergroups as defined herein, or a combination thereof.

In some embodiments of the present invention, the aliphatic radicalshave from about 1 to about 50 carbon atoms, from about 2 to about 40carbon atoms, from about 3 to about 30 carbon atoms, from about 4 toabout 20 carbon atoms, from about 5 to about 15 carbon atoms, from about6 to about 10 carbon atoms, and any range therein. In some embodiments,the aromatic radicals have from about 4 to about 200 carbon atoms, fromabout 6 to about 150 carbon atoms, from about 12 to about 120 carbonatoms, from about 18 to about 90 carbon atoms, from about 24 to about 60carbon atoms, and any range therein.

The term “alkyl” refers to a straight-chained or branched hydrocarbonchain. Examples of alkyl groups include lower alkyl groups such as, forexample, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,t-butyl or iso-hexyl; upper alkyl groups such as for example, n-heptyl,n-octyl, iso-octyl, nonyl, decyl, and the like; lower alkylene such as,for example, ethylene, propylene, propylyne, butylenes, butadiene,pentene, n-hexene and iso-hexene; and upper alkylene such as, forexample, n-heptene, n-octene, iso-octene, nonene, decene, and the like.Persons of ordinary skill in the art are familiar with numerousstraight-chained and branched alkyl groups, which are within the scopeof the present invention. In addition, such alkyl groups may alsocontain various substituents in which one or more hydrogen atoms isreplaced by a functional group, or the alkyl groups can contain anin-chain functional group. The phrase “straight-chained or branched”includes any substituted or unsubstituted acyclic carbon-containingcompounds including, but not limited to, alkanes, alkenes and alkynes.

The term “alkenyl” refers to a straight-chained or branched hydrocarbonchain including at least one alkene functionality. The term “alkynyl”refers to a straight-chained or branched carbon-containing chainincluding at least one alkyne functionality. The term “aryl” refers to acarbon-containing ring bearing a system of conjugated double bonds oftencomprising at least six π (pi) electrons. Examples of aryl groupsinclude, but are not limited to, phenyl, naphthyl, anysyl, toluyl,xylenyl, and the like. The term “aralkyl” refers to an alkyl groupsubstituted with at least one aryl group. The term “aralkenyl” refers toan alkenyl group substituted with at least one aryl group.

A radical is “straight-chained” when it has less than 0.1 mole percentof sidechains having 1 or more carbon atoms. In some embodiments, aradical is straight-chained if it has less than 0.01 mole percent ofsuch sidechains. In other embodiments, a radical is straight-chained ifit has less than 0.001 mole percent of such sidechains. A radical is“branched” when it has more than 0.1 mole percent of sidechains having 1or more carbon atoms. In some embodiments, a radical is branched when ithas more than 0.01 mole percent of such sidechains. In otherembodiments, a radical is branched when it has more than 0.001 molepercent of such sidechains.

The terms “radical,” “group,” “functional group,” and “substituent” canbe used interchangeably in some contexts and can be used together tofurther describe a chemical structure. For example, the term “functionalgroup” can refer to a chemical “group” or “radical,” which is a chemicalstructure variable that can be in-chain, pendant and/or terminal to thechemical structure. A functional group may be substituted. Examples ofsubstituents in substituted radicals include, but are not limited to,hydroxyls, alkyls, carboxyls, esters, aminos, amidos, iminos andcombinations thereof. Such a functional group can also, for example,contain a heteroatom. Examples of heteroatoms of the hetero-radicalsinclude, but are not limited to, sulfur, phosphorous, oxygen, nitrogenand combinations thereof.

In some embodiments, the functional groups can include, but are notlimited to, oxygen-containing groups such as, for example, alcohols,ethers, phenols, and derivatives thereof. Such oxygen-containing groupsinclude, but are not limited to, acetonides, alcohols, alkoxides,bisphenols, carbinols, cresols, diols, enols, enolates, epoxides,ethers, glycols, hydroperoxides, peroxides, phenols, phenolates,phenoxides, pinacols, trioxides, and ynols.

In other embodiments, the functional groups can include, but are notlimited to, oxygen-containing groups such as, for example, aldehydes,ketones, quinones and derivatives thereof. Such oxygen-containing groupsinclude, but are not limited to, acetals, acyloins, aldehydes, carbonylcompounds, diosphenols, dypnones, hemiacetals, hemiketals, ketals,ketenes, keto compounds, ketones, quinhydrones, quinomethanes, quinines,and combinations thereof.

In other embodiments, the functional groups can be oxygen-containinggroups including, but not limited to, carboxylic acids, oxoacids,sulfonic acids, acid anhydrides, acid thioanhydrides, acyl groups, acylhalides, acylals, anhydrides, carboxylic acids, cyclic acid anhydrides,cyclic anhydrides, esters, fulgides, lactides, lactols, lactones,macrolides, naphthenic acids, ortho acids, ortho esters, oxo carboxylicacids, peroxy acids, and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, nitrogen-containing groups containing one nitrogen such as,for example, aldimines, aldoximes, alkoxyamines, amic acids, amides,amines, amine oxides, amine ylides, carbamates, hemiaminals,carbonitriles, carboxamides, isocyanides, cyanates, isocyanates,diisocyanates, cyanides, cyanohydrins, diacylamines, enamines,fulminates, hemiaminals, hydroxamic acids, hydroximic acids,hydroxylamines, imides, imidic acids, imidines, imines, oximes,isoureas, ketenimines, ketimines, ketoximes, lactams, lactims, nitriles,nitro, nitroso, nitrosolic acids, oxime O-ethers, quaternary ammoniumcompounds, quinone imines, quinonoximes, azomethines, ureides,urethanes, and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, nitrogen-containing groups containing two or more nitrogenssuch as, for example, aldazines, amide hydrazones, amide oximes,amidines, amidrazones, aminals, amine imides, amine imines, isodiazenes,azans, azides, azo imides, azines, azo compounds, azomethine imides,azoxy compounds, carbodiimides, carboxamidines, diamidides, diazocompounds, diazoamino compounds, diazoates, diazooxides, formamidinedisulfides, formazans, hydrazides, hydrazide hydrazones, hydrazideimides, hydrazidines, hydrazines, hydrazo compounds, hydrazones,ketazines, nitramines, nitrile imines, nitrimines, nitrolic acids,nitrosamides, nitrosamines, nitrosimines, ortho amides, semicarbazones,semioxamazones, triazanes, triazenes, and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, sulfur-containing groups such as sulfones, sulfides,sulfinamides, sulfilimines, sulfimides, sulfinamides, sulfinamidines,sulfines, sulfinic acids, sulfinic anhydrides, sulfinylamines,sulfonamides, sulfones, sulfonediimines, sulfonic acids, sulfonicanhydrides, sulfoxides, sulfoximides, sulphur diimides, thio,thioacetals, thioaldehydes, thioanhydrides, thiocarboxylic acids,thiocyanates, thioether, thiohemiacetals, thioketones, thiol, thiolates,xanthic acids, and combinations thereof.

In other embodiments, the functional groups can include, but are notlimited to, silyl groups, halogens, selenoethers, trifluoromethyls,thio-derivatives of urethanes where at least one oxygen atom is replacedby a sulfur atom, phosphoryls, phosphonates, phosphinates, andcombinations thereof. In other embodiments, the functional groups arecapable of free-radical polymerization and can include, but are notlimited to, ethylenically unsaturated groups such as, for example,allyl, vinyl, acryloyl and methacrylol, and maleate and maleimido; andcombinations thereof. In other embodiments, the functional groupsinclude halides. In other embodiments, the functional group may includelight scattering groups, magnetic groups, nanogold, other proteins, asolid matrix, radiolabels, carbohydrates, and combinations thereof.

The Agents

Biobeneficial and Bioactive Agents

A “bioactive agent” is a moiety that can be combined with a polymer andprovides a therapeutic effect, a prophylactic effect, both a therapeuticand a prophylactic effect, or other biologically active effect within asubject. Moreover, the bioactive agents of the present invention mayremain linked to a portion of the polymer or be released from thepolymer. A “biobeneficial agent” is an agent that can be combined with apolymer and provide a biological benefit within a subject withoutnecessarily being released from the polymer.

In one example, a biological benefit may be that the polymer or coatingbecomes non-thrombogenic, such that protein absorption is inhibited orprevented to avoid formation of a thromboembolism; promotes healing,such that endothelialization within a blood vessel is not exuberant butrather forms a healthy and functional endothelial layer; or isnon-inflammatory, such that the biobeneficial agent acts as a biomimicto passively avoid attracting monocytes and neutrophils, which couldlead to an event or cascade of events that create inflammation.

A “diagnostic agent” is a type of bioactive agent that can be used, forexample, in diagnosing the presence, nature, or extent of a disease ormedical condition in a subject. In one embodiment, a diagnostic agentcan be any agent that may be used in connection with methods for imagingan internal region of a patient and/or diagnosing the presence orabsence of a disease in a patient. Diagnostic agents include, forexample, contrast agents for use in connection with ultrasound imaging,magnetic resonance imaging (MRI), nuclear magnetic resonance (NMR),computed tomography (CT), electron spin resonance (ESR), nuclear medicalimaging, optical imaging, elastography, and radiofrequency (RF) andmicrowave lasers. Diagnostic agents may also include any other agentsuseful in facilitating diagnosis of a disease or other condition in apatient, whether or not imaging methodology is employed.

Examples of biobeneficial agents include, but are not limited to, manyof the polymers listed above such as, for example,carboxymethylcellulose; poly(alkylene glycols) such as, for example,PEG; poly(N-vinyl pyrrolidone); poly(acrylamide methyl propane sulfonicacid); poly(styrene sulfonate); sulfonated polysaccharides such as, forexample, sulfonated dextran; sulfated polysaccharides such as, forexample, sulfated dextran and dermatan sulfate; and glycosaminoglycanssuch as, for example, hyaluronic acid and heparin; and any derivatives,analogs, homologues, congeners, salts, copolymers and combinationsthereof. In some embodiments, the biobeneficial agents can be prohealingsuch as, for example, poly(ester amides), elastin, silk-elastin,collagen, atrial natriuretic peptide (ANP); and peptide sequences suchas, for example, those comprising Arg-Gly-Asp (RGD). In otherembodiments, the biobeneficial agents can be non-thrombotics such as,for example, thrombomodulin; and antimicrobials such as, for example,the organosilanes. It is to be appreciated that one skilled in the artshould recognize that some of the groups, subgroups, and individualbiobeneficial agents may not be used in some embodiments of the presentinvention.

Examples of heparin derivatives include, but are not limited to, earthmetal salts of heparin such as, for example, sodium heparin, potassiumheparin, lithium heparin, calcium heparin, magnesium heparin, and lowmolecular weight heparin. Other examples of heparin derivatives include,but are not limited to, heparin sulfate, heparinoids, heparin-basedcompounds and heparin derivatized with hydrophobic materials.

Examples of hyaluronic acid derivates include, but are not limited to,sulfated hyaluronic acid such as, for example, O-sulphated orN-sulphated derivatives; esters of hyaluronic acid wherein the esterscan be aliphatic, aromatic, arylaliphatic, cycloaliphatic, heterocyclicor a combination thereof; crosslinked esters of hyaluronic acid whereinthe crosslinks can be formed with hydroxyl groups of a polysaccharidechain; crosslinked esters of hyaluronic acid wherein the crosslinks canbe formed with polyalcohols that are aliphatic, aromatic, arylaliphatic,cycloaliphatic, heterocyclic, or a combination thereof; hemiesters ofsuccinic acid or heavy metal salts thereof; quaternary ammonium salts ofhyaluronic acid or derivatives such as, for example, the O-sulphated orN-sulphated derivatives.

Examples of poly(alkylene glycols) include, but are not limited to, PEG,mPEG, poly(ethylene oxide), poly(propylene glycol)(PPG),poly(tetramethylene glycol), and any derivatives, analogs, homologues,congeners, salts, copolymers and combinations thereof. In someembodiments, the poly(alkylene glycol) is PEG. In other embodiments, thepoly(alkylene glycol) is mPEG. In other embodiments, the poly(alkyleneglycol) is poly(ethylene glycol-co-hydroxybutyrate).

The copolymers that may be used as biobeneficial agents include, but arenot limited to, any derivatives, analogs, homologues, congeners, salts,copolymers and combinations of the foregoing examples of agents.Examples of copolymers that may be used as biobeneficial agents in thepresent invention include, but are not limited to, dermatan sulfate,which is a copolymer of D-glucuronic acid or L-iduronic acid andN-acetyl-D-galactosamine; poly(ethylene oxide-co-propylene oxide);copolymers of PEG and hyaluronic acid; copolymers of PEG and heparin;copolymers of PEG and hirudin; graft copolymers of poly(L-lysine) andPEG; copolymers of PEG and a poly(hydroxyalkanoate) such as, forexample, poly(ethylene glycol-co-hydroxybutyrate); and, any derivatives,analogs, congeners, salts, or combinations thereof. In some embodiments,the copolymer that may be used as a biobeneficial agent can be acopolymer of PEG and hyaluronic acid, a copolymer of PEG and hirudin,and any derivative, analog, congener, salt, copolymer or combinationthereof. In other embodiments, the copolymer that may be used as abiobeneficial agent is a copolymer of PEG and a poly(hydroxyalkanoate)such as, for example, poly(hydroxybutyrate); and any derivative, analog,congener, salt, copolymer or combination thereof.

The bioactive agents can be any moiety capable of contributing to atherapeutic effect, a prophylactic effect, both a therapeutic andprophylactic effect, or other biologically active effect in a mammal.The agent can also have diagnostic properties. The bioactive agentsinclude, but are not limited to, small molecules, nucleotides,oligonucleotides, polynucleotides, amino acids, oligopeptides,polypeptides, and proteins. In one example, the bioactive agent inhibitsthe activity of vascular smooth muscle cells. In another example, thebioactive agent controls migration or proliferation of smooth musclecells to inhibit restenosis.

Bioactive agents include, but are not limited to, antiproliferatives,antineoplastics, antimitotics, anti-inflammatories, antiplatelets,anticoagulants, antifibrins, antithrombins, antibiotics, antiallergics,antioxidants, and any prodrugs, metabolites, analogs, homologues,congeners, derivatives, salts and combinations thereof. It is to beappreciated that one skilled in the art should recognize that some ofthe groups, subgroups, and individual bioactive agents may not be usedin some embodiments of the present invention.

Antiproliferatives include, for example, actinomycin D, actinomycin IV,actinomycin I₁, actinomycin X₁, actinomycin C₁, and dactinomycin(COSMEGEN®, Merck & Co., Inc.). Antineoplastics or antimitotics include,for example, paclitaxel (TAXOL®, Bristol-Myers Squibb Co.), docetaxel(TAXOTERE®, Aventis S.A.), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (ADRIAMYCIN®,Pfizer, Inc.) and mitomycin (MUTAMYCIN®, Bristol-Myers Squibb Co.), andany prodrugs, metabolites, analogs, homologues, congeners, derivatives,salts and combinations thereof.

Antiplatelets, anticoagulants, antifibrin, and antithrombins include,for example, sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors (ANGIOMAX®, Biogen, Inc.), and any prodrugs, metabolites,analogs, homologues, congeners, derivatives, salts and combinationsthereof.

Cytostatic or antiproliferative agents include, for example,angiopeptin, angiotensin converting enzyme inhibitors such as captopril(CAPOTEN® and CAPOZIDE®, Bristol-Myers Squibb Co.), cilazapril orlisinopril (PRINIVIL® and PRINZIDE®, Merck & Co., Inc.); calcium channelblockers such as nifedipine; colchicines; fibroblast growth factor (FGF)antagonists, fish oil (omega 3-fatty acid); histamine antagonists;lovastatin (MEVACOR®, Merck & Co., Inc.); monoclonal antibodiesincluding, but not limited to, antibodies specific for Platelet-DerivedGrowth Factor (PDGF) receptors; nitroprusside; phosphodiesteraseinhibitors; prostaglandin inhibitors; suramin; serotonin blockers;steroids; thioprotease inhibitors; PDGF antagonists including, but notlimited to, triazolopyrimidine; and nitric oxide, and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof. Antiallergic agents include, but are not limitedto, pemirolast potassium (ALAMAST®, Santen, Inc.), and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof.

Other bioactive agents useful in the present invention include, but arenot limited to, free radical scavengers; nitric oxide donors; rapamycin;methyl rapamycin; 42-Epi-(tetrazoylyl)rapamycin (ABT-578); everolimus;tacrolimus; 40-O-(2-hydroxy)ethyl-rapamycin;40-O-(3-hydroxy)propyl-rapamycin;40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tetrazole containingrapamycin analogs such as those described in U.S. Pat. No. 6,329,386;estradiol; clobetasol; idoxifen; tazarotene; alpha-interferon; hostcells such as epithelial cells; genetically engineered epithelial cells;dexamethasone; and, any prodrugs, metabolites, analogs, homologues,congeners, derivatives, salts and combinations thereof.

Free radical scavengers include, but are not limited to,2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical (TEMPO);4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical(4-amino-TEMPO); 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, freeradical (TEMPOL), 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxymethyl sulfate, free radical; 16-doxyl-stearic acid, free radical;superoxide dismutase mimic (SODm) and any analogs, homologues,congeners, derivatives, salts and combinations thereof. Nitric oxidedonors include, but are not limited to, S-nitrosothiols, nitrites,N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazeniumdiolates such as spermine diazenium diolate and any analogs, homologues,congeners, derivatives, salts and combinations thereof.

Examples of diagnostic agents include radioopaque materials and include,but are not limited to, materials comprising iodine oriodine-derivatives such as, for example, iohexal and iopamidol, whichare detectable by x-rays. Other diagnostic agents such as, for example,radioisotopes, are detectable by tracing radioactive emissions. Otherdiagnostic agents may include those that are detectable by magneticresonance imaging (MRI), ultrasound and other imaging procedures suchas, for example, fluorescence and positron emission tomagraphy (PET).Examples of agents detectable by MRI are paramagnetic agents, whichinclude, but are not limited to, gadolinium chelated compounds. Examplesof agents detectable by ultrasound include, but are not limited to,perflexane. Examples of fluorescence agents include, but are not limitedto, indocyanine green. Examples of agents used in diagnostic PETinclude, but are not limited to, fluorodeoxyglucose, sodium fluoride,methionine, choline, deoxyglucose, butanol, raclopride, spiperone,bromospiperone, carfentanil, and flumazenil.

Plasticizing Agents

The terms “plasticizer” and “plasticizing agent” can be usedinterchangeably in the present invention, and refer to any agent,including any agent described above, where the agent can be added to apolymeric composition to modify the mechanical properties of thecomposition or a product formed from the composition. Plasticizers canbe added, for example, to reduce crystallinity, lower theglass-transition temperature (T_(g)), or reduce the intermolecularforces between polymers, with design goals that may include, but are notlimited to, enhancing mobility between polymer chains in thecomposition. The mechanical properties that are modified include, butare not limited to, Young's modulus, impact resistance (toughness),tensile strength, and tear strength. Impact resistance, or “toughness,”is a measure of energy absorbed during fracture of a polymer sample ofstandard dimensions and geometry when subjected to very rapid impactloading. Toughness can be measured using Charpy and Izod impact tests toassess the brittleness of a material.

A plasticizer can be monomeric, polymeric, co-polymeric, or acombination thereof, and can be combined with a polymeric composition inthe same manner as described above for the biobeneficial and bioactiveagents. Plasticization and solubility are analogous in the sense thatselecting a plasticizer involves considerations similar to selecting asolvent such as, for example, polarity. Furthermore, plasticization canalso be provided through covalent bonding by changing the molecularstructure of the polymer through copolymerization.

Examples of plasticizing agents include, but are not limited to, lowmolecular weight polymers such as single-block polymers, multi-blockpolymers, and copolymers; oligomers such as ethyl-terminated oligomersof lactic acid; small organic molecules; hydrogen bond forming organiccompounds with and without hydroxyl groups; polyols such as lowmolecular weight polyols having aliphatic hydroxyls; alkanols such asbutanols, pentanols and hexanols; sugar alcohols and anhydrides of sugaralcohols; polyethers such as poly(alkylene glycols); esters such ascitrates, phthalates, sebacates and adipates; polyesters; aliphaticacids; proteins such as animal proteins and vegetable proteins; oilssuch as, for example, the vegetable oils and animal oils; silicones;acetylated monoglycerides; amides; acetamides; sulfoxides; sulfones;pyrrolidones; oxa acids; diglycolic acids; and any analogs, derivatives,copolymers and combinations thereof.

In some embodiments, the plasticizers include, but are not limited toother polyols such as, for example, caprolactone diol, caprolactonetriol, sorbitol, erythritol, glucidol, mannitol, sorbitol, sucrose, andtrimethylol propane. In other embodiments, the plasticizers include, butare not limited to, glycols such as, for example, ethylene glycol,diethylene glycol, triethylene glycol, tetraethylene glycol, propyleneglycol, butylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, pentamethylene glycol, hexamethylene glycol;glycol-ethers such as, for example, monopropylene glycol monoisopropylether, propylene glycol monoethyl ether, ethylene glycol monoethylether, and diethylene glycol monoethyl ether; and any analogs,derivatives, copolymers and combinations thereof.

In other embodiments, the plasticizers include, but are not limited toesters such as glycol esters such as, for example, diethylene glycoldibenzoate, dipropylene glycol dibenzoate, triethylene glycolcaprate-caprylate; monostearates such as, for example, glycerolmonostearate; citrate esters; organic acid esters; aromatic carboxylicesters; aliphatic dicarboxylic esters; fatty acid esters such as, forexample, stearic, oleic, myristic, palmitic, and sebacic acid esters;triacetin; poly(esters) such as, for example, phthalate polyesters,adipate polyesters, glutate polyesters, phthalates such as, for example,dialkyl phthalates, dimethyl phthalate, diethyl phthalate, isopropylphthalate, dibutyl phthalate, dihexyl phthalate, dioctyl phthalate,diisononyl phthalate, and diisodecyl phthalate; sebacates such as, forexample, alkyl sebacates, dimethyl sebacate, dibutyl sebacate;hydroxyl-esters such as, for example, lactate, alkyl lactates, ethyllactate, butyl lactate, allyl glycolate, ethyl glycolate, and glycerolmonostearate; citrates such as, for example, alkyl acetyl citrates,triethyl acetyl citrate, tributyl acetyl citrate, trihexyl acetylcitrate, alkyl citrates, triethyl citrate, and tributyl citrate; estersof castor oil such as, for example, methyl ricinolate; aromaticcarboxylic esters such as, for example, trimellitic esters, benzoicesters, and terephthalic esters; aliphatic dicarboxylic esters such as,for example, dialkyl adipates, alkyl allylether diester adipates,dibutoxyethoxyethyl adipate, diisobutyl adipate, sebacic esters, azelaicesters, citric esters, and tartaric esters; and fatty acid esters suchas, for example, glycerol, mono- di- or triacetate, and sodium diethylsulfosuccinate; and any analogs, derivatives, copolymers andcombinations thereof.

In other embodiments, the plasticizers include, but are not limited toethers and polyethers such as, for example, poly(alkylene glycols) suchas poly(ethylene glycols) (PEG), poly(propylene glycols), andpoly(ethylene/propylene glycols); low molecular weight poly(ethyleneglycols) such as, for example, PEG 400 and PEG 6000; PEG derivativessuch as, for example, methoxy poly(ethylene glycol) (mPEG); andester-ethers such as, for example, diethylene glycol dibenzoate,dipropylene glycol dibenzoate, and triethylene glycol caprate-caprylate;and any analogs, derivatives, copolymers and combinations thereof.

In other embodiments, the plasticizers include, but are not limited to,amides such as, for example, oleic amide, erucic amide, and palmiticamide; alkyl acetamides such as, for example, dimethyl acetamide anddimethyl formamide; sulfoxides such as for example, dimethyl sulfoxide;pyrrolidones such as, for example, n-methyl pyrrolidone; sulfones suchas, for example, tetramethylene sulfone; acids such as, for example, oxamonoacids, oxa diacids such as 3,6,9-trioxaundecanedioic acid, polyoxadiacids, ethyl ester of acetylated citric acid, butyl ester ofacetylated citric acid, capryl ester of acetylated citric acid, anddiglycolic acids such as dimethylol propionic acid; and any analogs,derivatives, copolymers and combinations thereof.

In other embodiments, the plasticizers can be vegetable oils including,but not limited to, epoxidized soybean oil; linseed oil; castor oil;coconut oil; fractionated coconut oil; epoxidized tallates; and estersof fatty acids such as stearic, oleic, myristic, palmitic, and sebacicacid. In other embodiments, the plasticizers can be essential oilsincluding, but not limited to, angelica oil, anise oil, arnica oil,aurantii aetheroleum, valerian oil, basilici aetheroleum, bergamot oil,savory oil, bucco aetheroleum, camphor, cardamomi aetheroleum, cassiaoil, chenopodium oil, chrysanthemum oil, cinae aetheroleum, citronellaoil, lemon oil, citrus oil, costus oil, curcuma oil, carlina oil, elemioil, tarragon oil, eucalyptus oil, fennel oil, pine needle oil, pineoil, filicis, aetheroleum, galbanum oil, gaultheriae aetheroleum,geranium oil, guaiac wood oil, hazelwort oil, iris oil, hypericum oil,calamus oil, camomile oil, fir needle oil, garlic oil, coriander oil,carraway oil, lauri aetheroleum, lavender oil, lemon grass oil, lovageoil, bay oil, lupuli strobuli aetheroleum, mace oil, marjoram oil,mandarine oil, melissa oil, menthol, millefolii aetheroleum, mint oil,clary oil, nutmeg oil, spikenard oil, clove oil, neroli oil, niaouli,olibanum oil, ononidis aetheroleum, opopranax oil, orange oil, oreganooil, orthosiphon oil, patchouli oil, parsley oil, petit-grain oil,peppermint oil, tansy oil, rosewood oil, rose oil, rosemary oil, rueoil, sabinae aetheroleum, saffron oil, sage oil, sandalwood oil,sassafras oil, celery oil, mustard oil, serphylli aetheroleum,immortelle oil, fir oil, teatree oil, terpentine oil, thyme oil, juniperoil, frankincense oil, hyssop oil, cedar wood oil, cinnamon oil, andcypress oil; and other oils such as, for example, fish oil; and, anyanalogs, derivatives, copolymers and combinations thereof.

The molecular weights of the plasticizers can vary. In some embodiments,the molecular weights of the plasticizers range from about 10 Daltons toabout 50,000 Daltons; from about 25 Daltons to about 25,000 Daltons;from about 50 Daltons to about 10,000 Daltons; from about 100 Daltons toabout 5,000 Daltons; from about 200 Daltons to about 2500 Daltons; fromabout 400 Daltons to about 1250 Daltons; and any range therein. In otherembodiments, the molecular weights of the plasticizers range from about400 Daltons to about 4000 Daltons; from about 300 Daltons to about 3000Daltons; from about 200 Daltons to about 2000 Daltons; from about 100Daltons to about 1000 Daltons; from about 50 Daltons to about 5000Daltons; and any range therein. The molecular weights are taught hereinas a number average molecular weight.

The amount of plasticizer used in the present invention, can range fromabout 0.001% to about 70%; from about 0.01% to about 60%; from about0.1% to about 50%; from about 0.1% to about 40%; from about 0.1% toabout 30%; from about 0.1% to about 25%; from about 0.1% to about 20%;from about 0.1% to about 10%; from about 0.4% to about 40%; from about0.6% to about 30%; from about 0.75% to about 25%; from about 1.0% toabout 20%; and any range therein, as a weight percentage based on thetotal weight of the polymer and agent or combination of agents.

It should be appreciated that any one or any combination of theplasticizers described above can be used in the present invention. Forexample, the plasticizers can be combined to obtain the desiredfunction. In some embodiments, a secondary plasticizer is combined witha primary plasticizer in an amount that ranges from about 0.001% toabout 20%; from about 0.01% to about 15%; from about 0.05% to about 10%;from about 0.75% to about 7.5%; from about 1.0% to about 5%, or anyrange therein, as a weight percentage based on the total weight of thepolymer any agent or combination of agents.

It should also be appreciated that the plasticizers can be combined withother active agents to obtain other desired functions such as, forexample, an added therapeutic, prophylactic, and/or diagnostic function.In some embodiments, the plasticizers can be linked to other agentsthrough ether, amide, ester, orthoester, anhydride, ketal, acetal,carbonate, and all-aromatic carbonate linkages, which are discussed inmore detail below.

In some embodiments, the agents can be chemically connected to a polymerby covalent bonds. In other embodiments, the agents can be chemicallyconnected to a polymer by non-covalent bonds such as, for example, byionic bonds, inter-molecular attractions, or a combination thereof. Inother embodiments, the agents can be physically connected to a polymer.In other embodiments, the agents can be chemically and physicallyconnected with a polymer.

Examples of ionic bonding can include, but are not limited to, ionicbonding of an anionic agent to a cationic site on a polymer or acationic agent to an anionic site on a polymer. In some embodiments, ananionic agent can be bound to a quaternary amine on a polymer. In otherembodiments, an agent with a quaternary amine can be bound to an anionicsite on a polymer. Examples of inter-molecular attractions include, butare not limited to, hydrogen bonding such as, for example, the permanentdipole interactions between hydroxyl, amino, carboxyl, and sulfhydrylgroups, and combinations thereof. Examples of physical connections caninclude, but are not limited to, interpenetrating networks and chainentanglement. The agents can also be blended or mixed with the PHAcompositions.

In some embodiments, the agents have a reactive group that can be usedto link the agents to the polymer. Examples of reactive groups include,but are not limited to, hydroxyl, acyl, amino, amido, and sulfhydrylgroups. In some embodiments, the agents can be released or can separatefrom the polymer composition. In other embodiments, the agents can bebiobeneficial, bioactive, diagnostic, plasticizing, or have acombination of these characteristics.

In some embodiments, the molecular weight of an agent should be at orbelow about 40,000 Daltons, or any range therein, to ensure eliminationof the agent from a mammal. In one embodiment, the molecular weight ofthe agent ranges from about 300 Daltons to about 40,000 Daltons, fromabout 8,000 Daltons to about 30,000 Daltons, from about 10,000 Daltonsto about 20,000 Daltons, or any range therein. If upon release, thebiobeneficial agent is rapidly broken down in the body, then themolecular weight of the agent could be greater than about 40,000 Daltonswithout compromising patient safety. The molecular weights as taughtherein are a number average molecular weight.

It should also be appreciated that the agents of the present inventioncan have properties that are biobeneficial, bioactive, diagnostic,plasticizing or a combination thereof. For example, classification of anagent as a biobeneficial agent does not preclude the use of that agentas a bioactive agent, diagnostic agent and/or plasticizing agent.Likewise, classification of an agent as a bioactive agent does notpreclude the use of that agent as a diagnostic agent, biobeneficialagent and/or plasticizing agent. Furthermore, classification of an agentas a plasticizing agent does not preclude the use of that agent as abiobeneficial agent, bioactive agent, and/or diagnostic agent. It shouldalso be appreciated that any of the foregoing agents can be combinedwith the PHA compositions such as, for example, in the form of a medicaldevice or a coating for a medical device. By way of a non-limitingexample, a stent coated with the PHA compositions of the invention cancontain paclitaxel, docetaxel, rapamycin, methyl rapamycin, ABT-578, oreverolimus.

Concentrations of Agents

The agents of the present invention can be combined with other agents toobtain other desired functions of the polymeric compositions. Theamounts of the agents that compose the polymeric compositions varyaccording to a variety of factors including, but not limited to, thebiological activity of the agent; the age, body weight, response, or thepast medical history of the subject; the type of atheroscleroticdisease; the presence of systemic diseases such as, for example,diabetes; the pharmacokinetic and pharmacodynamic effects of the agentsor combination of agents; and the design of the compositions forsustained release of the agents. Factors such as these are routinelyconsidered by one of skill in the art when administering an agent to asubject.

It is to be appreciated that the design of a composition for thesustained release of agents can be dependent on a variety of factorssuch as, for example, the therapeutic, prophylactic, ameliorative ordiagnostic needs of a patient. In some embodiments, the agent cancomprise an antiproliferative and should have a sustained releaseranging from about 1 week to about 10 weeks, from about 2 weeks to about8 weeks, from about 3 weeks to about 7 weeks, from about 4 weeks toabout 6 weeks, and any range therein. In other embodiments, the agentcan comprise an anti-inflammatory and should have a sustained releaseranging from about 6 hours to about 3 weeks, from about 12 hours toabout 2 weeks, from about 18 hours to about 10 days, from about 1 day toabout 7 days, from about 2 days to about 6 days, or any range therein.In general, the sustained release should range from about 4 hours toabout 12 weeks; alternatively, from about 6 hours to about 10 weeks; orfrom about 1 day to about 8 weeks.

Effective amounts, for example, may be extrapolated from in vitro oranimal model systems. In some embodiments, the agent or combination ofagents have a concentration that ranges from about 0.001% to about 75%;from about 0.01% to about 70%; from about 0.1% to about 60%; from about0.25% to about 60%; from about 0.5% to about 50%; from about 0.75% toabout 40%; from about 1.0% to about 30%; from about 2% to about 20%;and, any range therein, where the percentage is based on the totalweight of the polymer and agent or combination of agents.

The Structures of PHAs, Copolymers and Agents

The term “PHA” refers to a polymeric composition that contains ahydroxyalkanoate, which is a hydroxyacid moiety that contains an alkanewith hydroxyl and carboxyl functionality. Many known PHA compositionsare brittle by themselves and, as taught herein, their physical andmechanical properties can be modified by combining other components inthe compositions. The combinations, as described above, can result in,for example, novel blends, mixtures, and other combinations thatinclude, but are not limited to, copolymers such as, for example,in-chain and pendant copolymers.

Copolymers can be designed to perform in a desired manner in thebiological organism. For example, copolymers can offer stability inperformance, since some blends and mixtures can include agents that willleach at a rate that is faster than desired. An example of a compositionthat is improved through copolymerization is the combination of PEG witha polymer. While not intending to be bound by any theory or mechanism ofaction, the formation of copolymers can prevent the formation ofdiscrete phases by a phase separation that may otherwise occur in such ablend or mixture of hydrophobic and hydrophilic materials, allowing fora much higher concentration of a component such as, for example, PEG, tobe added to a PHA to obtain a desired property. Phase separation canlead to a fast drug release and/or poor mechanical properties.

In some embodiments, the compositions of the present invention can bedesigned for a predetermined degree of crystallinity that can bereproducible. While not intending to be bound by any theory or mechanismof action, the degree of crystallinity can affect the water swelling andhydrolytic lability of a polymer, thus affecting the bioadsorption rateand rate of release of an agent. In other embodiments, the compositionsof the present invention can be designed to exhibit surface erosionrather than bulk erosion in order to, for example, provide a product,such as an agent-releasing stent or coating that may be considered moredesirable in some applications.

A polymer of the present invention can comprise a polymeric carrierhaving an A-moiety (A), a B-moiety (B), and an optional linkage (L₁)connecting A to B. The polymeric carrier may further comprise an agent(X), and a linkage (L₂) connecting X to the polymer. The PHA-agentcombination can be generally represented by formula (I):

In formula (I), the A:B ratio can be less than, greater than, or equalto one; both A and B can be independently selected, and comprise anycombination of monomers such that the polymer has at least onehydroxyalkanoate group. At least one of L₁, B, L₂ or X may comprise anagent that is bioactive and/or biobeneficial, wherein the agent alsoaffects a physical property and/or a mechanical property of acomposition comprising the polymer, and z is an integer not equal tozero.

In some embodiments, A can be represented by formula (II):

wherein the groups R₁ through R₄; and k, m, and n are defined above; andL₁, B, L₂, and X can include any polymer, agent, or combinationdescribed above. In some embodiments, at least one of L₁, B, L₂ or Xshould include an agent that is bioactive and/or biobeneficial, and theagent should also affect a physical property and/or a mechanicalproperty of a composition comprising the polymer. Such an agent can alsobe included as a blend or mixture with a PHA composition.

In some embodiments, the composition can comprise 3-hydroxybutyrate,4-hydroxybutyrate, 3-hydroxyvalerate, 3-hydroxybutyrate-co-valerate,caprolactone, lactide-co-glycolide, and combinations thereof. In otherembodiments, each R₁ can be independently selected from alkylenes,alkanoates, alkyl alkanoates, diesters, acylals, diacids, saturatedfatty acids, glycerides, and combinations thereof, provided that thereis at least one hydroxyalkanoate unit within the PHA composition afterthe selection of R₁; and, that the molar percent of the hydroxyalkanoatecomponent in the polymer is of an amount sufficient to produce a polymerwith a characteristic that is indicative of a poly(hydroxyalkanoate).The integer k can be selected to obtain this design characteristic.

In some embodiments, the characteristics that may be tested include, butare not limited to, biological characteristics, chemical characteristicsand mechanical characteristics. Biological characteristics include, butare not limited to, biodegradability and biocompatibility. Chemicalcharacteristics include, but are not limited to, spectral behavior whenanalyzed using continous-wave or Fourier transform analyses such as, forexample, Fourier transform infrared analysis (FTIR), Fourier transformnuclear magnetic resonance (FTNMR); thermal behavior when analyzedusing, for example, thermogravimetry, differential scanning calorimetry(TGA/DSC) and dynamic mechanical analysis (DMA); and surface behaviorwhen analyzed using, for example, electron spectroscopy for chemicalanalysis (ESCA), secondary ion mass spectroscopy (SIMS), scanningtunneling microscopy (STM), scanning force microscopy (SFM) using anatomic force microscope (AFM), and contact angle. Thermo-mechanicalcharacteristics include, but are not limited to, tensile strength, tearstrength, modulus, impact resistance (toughness), strain-to-failure,melting point, degree of crystallinity, and glass transition temperature(T_(g)).

In some embodiments, the molar percent of the hydroxyalkanoate componentshould range from about 40% to about 100%, from about 40% to about 95%,from about 40% to about 90%, from about 40% to about 85%, from about 40%to about 80%, from about 40% to about 75%, from about 40% to about 70%,from about 40% to about 65%, from about 40% to about 60%, or any rangetherein. In other embodiments, the molar percent of the PHA componentshould range from about 45% to about 100%, from about 50% to about 95%,from about 55% to about 90%, from about 60% to about 85%, from about 60%to about 80%, from about 60% to about 75%, from about 70% to about 100%,from about 70% to about 95%, from about 75% to about 95%, or any rangetherein.

In other embodiments, each R₁ can be independently selected fromalkylenes, alkanoates, alkyl alkanoates, diesters, acylals, diacids,saturated fatty acids, glycerides, and combinations thereof, providedthat there is at least one persistence length of hydroxyalkanoatecomponents, wherein a persistence length is a maximum length scalebeyond which a chain of hydroxyalkanoates is thought to begin losingrigidity. The persistence length is a measure that suggests, inter alia,the radius of gyration and entanglement potential of a polymer. In someembodiments, the persistence length ranges from about 0.5 nm to about200 nm, from about 0.75 nm to about 150 nm, from about 1.0 nm to about100 nm, from about 1.0 nm to about 75 nm, from about 1 nm to about 50nm, from about 1 nm to about 25 nm, and any range therein. The radius ofgyration of a polymer in solution can be measured using viscosity orsize-exclusion chromatography.

In other embodiments, each R₁ can be independently selected fromalkylenes, alkanoates, alkyl alkanoates, diesters, acylals, diacids,saturated fatty acids, glycerides, and combinations thereof, providedthat there is at least an oligomer of hydroxyalkanoate repeating unitspresent within the polymer, wherein an oligomer ranges in length fromabout 4 units to about 20 units, from about 6 units to about 20 units,from about 8 units to about 20 units, or any range therein.

The functional groups R₂ through R₄ can comprise any functional group oragent taught herein. In some embodiments, the functional groups presentin a PHA composition such as, for example, R₂ through R₄, can be used toattach an agent covalently or non-covalently; provide crosslinkingsites; assist in biodegradation of a PHA by serving as an electrondonating or withdrawing moiety; decrease immunogenicity; modifypharmacokinetics and pharmacodynamics such as the targeting of polymerfragments that may comprise agents, the solubility and bioavailabilityof polymer fragments and agents; and combinations thereof. In someembodiments, R₂ through R₄ can be independently selected from hydrogen;substituted, unsubstituted, hetero-, straight-chained, branched, cyclic,saturated and unsaturated aliphatic radicals; and substituted,unsubstituted, and hetero-aromatic radicals. The integer m is limited bythe integer k, can be selected to modify the characteristics of thepolymer to a predetermined degree, and can vary according to the typeand variety of functional groups that have been selected to meetparticular design considerations in the development of the polymer.

In other embodiments, the functional groups that can be included in R₂through R₄ contain oxygen-containing groups such as, for example,hydroxyls, carboxyls, alkoxyls, epoxyls, carbonyls, and combinationsthereof. In other embodiments, the functional groups that can beincluded in R₂ through R₄ contain nitrogen-containing groups such as,for example, amino, amido, nitro, isocyanato, azido, diazo, hydrazino,azo, azoxyl, cyano, and combinations thereof. In other embodiments, thefunctional groups that can be included in R₂ through R₄ containsulfur-containing groups such as, for example, thio, thiol, sulfide, andcombinations thereof. In other embodiments, the functional groups thatcan be included in R₂ through R₄ contain ethylenically unsaturatedgroups such as, for example, vinyl, allyl, acryloyl and methacrylol, andmaleate and maleimido.

In other embodiments, the functional groups that can be included in R₂through R₄ contain ethers, esters, orthoesters; anhydrides, ketones,urethanes, halogens, and combinations thereof. In all embodiments, thefunctional groups included in R₂ through R₄ may be any functional grouptaught herein, may likewise be substituted by any functional grouptaught herein, and may also contain a heteroatom. Examples ofheteroatoms include, but are not limited to, sulfur, phosphorous,oxygen, nitrogen and combinations thereof.

In some embodiments, the optional linkage L₁ can comprise a substituted,unsubstituted, hetero-, straight-chained, branched, cyclic, saturated orunsaturated aliphatic radical; and a substituted or unsubstitutedaromatic radical. In other embodiments, L₁ can comprise from about 0 toabout 50 carbon atoms, from about 2 to about 40 carbon atoms, from about3 to about 30 carbon atoms, from about 4 to about 20 carbon atoms, fromabout 5 to about 10 carbon atoms, and any range therein.

In other embodiments, the L₁ can comprise a non-carbon species such as,for example, a disulfide. In other embodiments, L₁ can comprisepoly(vinyl pyrrolidone); carboxymethylcellulose; poly(ethylene);polypropylene; hyaluronic acid; heparin; poly(styrene sulfonate);phosphorylcholine; substituted methacrylates; substituted orunsubstituted poly(alkylene glycols), which include, but are not limitedto, PEG, PEG derivatives such as mPEG, amino-terminated PEG,carboxyl-terminated PEG, and any other functionalized PEGs available inthe art; PPG, poly(tetramethylene glycol), poly(ethyleneoxide-co-propylene oxide), poly(ethylene glycol-co-hydroxybutyrate), orcopolymers and combinations thereof. In one embodiment, thepoly(alkylene glycol) is PEG. In another embodiment, the poly(alkyleneglycol) may comprise a PEG derivative such as amino-terminated PEG. Inanother embodiment, L₁ can comprise a co-polymer of PEG or a PEGderivative. In another embodiment, L₁ can comprise a co-polymer of PEGand heparin, a copolymer of PEG and hirudin, or combination thereof.

In other embodiments, the optional linkage L₂ can be used to connect Xto the polymer. The agent X can be connected to the polymer by L₂, whichcan be any interunit linkage. In some embodiments, L₂ can be an ether,an amide, an ester, an anhydride, an orthoester, an all-aromaticcarbonate, an acetal, a ketal, a urethane, a urea, a glycoside, adisulfide, a siloxane linkage, or a combination thereof. It is to beappreciated that some of these linkages may not be used in someembodiments of the present invention.

The selection of L₂ allows for control of the relative strength orstability of the bond between X and the polymeric carrier as compared tothe strength or stability of the bonds within the polymeric carrier.Such control allows for a controlled release of agents that aresubstantially free of attached molecules from the polymeric carrier. Theagent X can be biobeneficial, bioactive, diagnostic, plasticizing, or ahave a combination of these properties.

In some embodiments, L₁, B, L₂, X, or a combination thereof, can includea polyol, a polycarboxylic acid, an amino acid, or a combinationthereof. These moieties can be incorporated into a PHA to provide adesired chemical functionality for linking an agent; and/or, provide adesired physical/mechanical, bioactive or biobeneficial characteristic;or a combination thereof. The polyols used in the present invention maybe organic compounds having two or more hydroxyl groups. In someembodiments, the polyols include, but are not limited to,cyclohexanedimethanol, glycerol, trimethylolpropane, pentaerythritol andcompounds represented by formula (III):

wherein R can be a substituted, unsubstituted, hetero-,straight-chained, branched, cyclic, saturated or unsaturated aliphaticradical; or a substituted, unsubstituted, or hetero-aromatic radical;and i is an integer.

In some embodiments, the polyols are diols. Examples of diols that canbe used include ethylene glycol, 1,2-propanediol, 1,3-propanediol,1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol,1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol,1,12-dodecanediol, dihydroxyacetone, serinol, and cyclohexanedimethanolssuch as, for example, 1,4-cis-cyclohexanedimethanol. In otherembodiments, the diols can be aromatic diols such as, for example,1,4-benzenedimethanol (also known as p-phenylene dicarbinol or asp-xylene-α,α′-diol). In other embodiments, polyols such as glycerol,trimethylolpropane, pentaerythritol and sorbitol are useful as long asthe possibility of forming a crosslink is considered. Polyols can beselectively polymerized by protecting one or more groups to preventcrosslinking, intentionally forming a crosslink, or using chemistry thatis selective for particular reactive groups. In other embodiments,functional diols such as serinol and diacetone alcohol can also be used.

In other embodiments, R can be a substituted or unsubstitutedpoly(alkylene glycol), which includes, but are not limited to,poly(ethylene glycol) (PEG); a functionalized PEG such as, for example,amino-terminated PEG; PPG; poly(tetramethylene glycol); poly(ethyleneoxide-co-propylene oxide); poly(ethylene glycol-co-hydroxybutyrate); orcopolymers and combinations thereof. It is to be appreciated that oneskilled in the art should recognize that some of the groups, subgroups,and individual polyols may not be used in some embodiments of thepresent invention.

The PEGs can have molecular weights ranging from about 400 Daltons toabout 40,000 Daltons, from about 200 Daltons to about 20,000 Daltons,from about 400 Daltons to about 25,000 Daltons, from about 400 Daltonsto about 15,000 Daltons, from about 500 Daltons to about 10,000 Daltons,from about 750 Daltons to about 7500 Daltons, from about 1000 Daltons toabout 10,000 Daltons, from about 1000 Daltons to about 5000 Daltons, orany range therein. The molecular weights are taught herein as a numberaverage molecular weight.

The polycarboxylic acids used in the present invention may be organicacids having two or more carboxyl groups. In some embodiments, thepolycarboxylic acids include dicarboxylic acids and tricarboxylic acidsand may be aliphatic or aromatic structures. In one embodiment, thepolycarboxylic acids are represented by formula (IV):

wherein R is optional and can be a substituted, unsubstituted, hetero-,straight-chained, branched, cyclic, saturated or unsaturated aliphaticradical; and a substituted or unsubstituted aromatic radical; and i isan integer.

Examples of polycarboxylic acids include, but are not limited to, oxalicacid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelicacid, suberic acid, sebacic acid, azelaic acid, terephthalic acid,citric acid, maleic acid, fumaric acid and combinations thereof. It isto be appreciated that one skilled in the art should recognize that someof the groups, subgroups, and individual polycarboxylic acids may not beused in some embodiments of the present invention.

In some embodiments, R is a methylene [—(CH₂)_(y)—] or phenylene group[—C₆H₄—], where y is an integer between 0 and 16. In other embodiments,R can include a substituted or unsubstituted poly(alkylene glycol),which includes, but is not limited to, PEG, PEG derivatives such asamino-terminated PEG and carboxyl-terminated PEG; PPG;poly(tetramethylene glycol); poly(ethylene oxide-co-propylene oxide);poly(ethylene glycol-co-hydroxybutyrate); or copolymers and combinationsthereof. In other embodiments R can be aryl. In other embodiments, R canbe substituted with an epoxy group.

In other embodiments, the aromatic dicarboxylic acids can be an isomerof phthalic acid such as, for example, terephthalic acid, isophthalicacid, phthalic acid, and combinations thereof. In other embodiments, thephenyl ring of the aromatic dicarboxylic acid can be substitutes withother groups such as alkyl groups, alkoxy groups, halogen groups, andany other functional groups defined above that will not interfere withthe polymerization.

In some embodiments, the polyols and polycarboxylic acids can be used tocrosslink the PHAs of the present invention. In one example, the PHAsare combined with an excess of one or more diacids to providecarboxyl-terminated PHAs that can then be combined with diols tocrosslink the PHAs. In these embodiments, the crosslinked PHAs can serveas a network for the covalent or non-covalent attachments of agents,where the non-covalent attachment can be, inter alia, a physicalentrapment or physical entanglement of an agent in the crosslinkednetwork.

As with the polyols, care must be taken to control crosslinking whenusing polycarboxylic acids to produce the polyesters of the presentinvention, because crosslinking can produce a polymer that has a highviscosity, is gelled, or is otherwise difficult to process. In someembodiments, crosslinking can be controlled by selecting polycarboxylicacids that contain carboxyl groups with different reactivities. In otherembodiments, crosslinking can be controlled by stoichiometry or byhaving an excess of one reactant. In yet other embodiments, crosslinkingcan be controlled by protecting one or more of the carboxyl groups witha chemical moiety, such as, for example, by forming benzyl esters. Insome embodiments, the polycarboxylic acids include, but are not limitedto, 1,3,5-benzenetricarboxylic acid, tricarballylic acid, trimelliticacid and trimellitic anhydride. For example, combining trimelliticanhydride in a reaction with one equivalent of an amine or hydroxyfunctional compound can essentially functionalize, or protect, one ofthe carboxyl groups.

The amino acids used in the present invention may be organic compoundscomprising an amino group and a carboxyl group, and the amino group maybe primary or secondary. Examples of amino acids include, but are notlimited to, glycine, alanine, valine, leucine, isoleucine, methionine,phenylalanine, tyrosine, aspartic acid, glutamic acid, lysine, arginine,serine, threonine, cysteine, asparagine, proline, tryptophan, histidineand combinations thereof. In some embodiments, the amino acids arerepresented by formula (V):

wherein R may be a hydrogen; a substituted, unsubstituted, hetero-,straight-chained, branched, cyclic, saturated or unsaturated aliphaticradical; or a substituted, unsubstituted, or hetero-aromatic radical. Insome embodiments, R can be substituted, unsubstituted, or hetero-formsof methyl, iso-propyl, sec-butyl, iso-butyl, benzyl, or a combinationthereof.

In embodiments where R is substituted, examples of substitutentsinclude, but are not limited to, hydroxyl, carboxyl, amino, imino groupsand combinations thereof. In embodiments where R is heteroaliphatic,examples of heteroatoms include, but are not limited to, sulfur,phosphorous, oxygen, nitrogen and combinations thereof. In otherembodiments, R can comprise substituted or unsubstituted poly(alkyleneglycols), which include, but are not limited to, PEG, PEG derivativessuch as mPEG, PPG, poly(tetramethylene glycol), poly(ethyleneoxide-co-propylene oxide), poly(ethylene glycol-co-hydroxybutyrate), orcopolymers and combinations thereof.

In some embodiments, the amino acids may be limited to bifunctionalamino acids or trifunctional amino acids. In other embodiments, theamino acids may be limited to diamines or triamines. In otherembodiments, the amino acids may be limited to monocarboxylics ordicarboxylics. In other embodiments, the amino acids may be limited toaliphatics. In other embodiments, the amino acids may be limited toaromatics. In other embodiments, the amino acids may be limited toamides. It is to be appreciated that one skilled in the art shouldrecognize that some of the groups, subgroups, and individual amino acidsmay not be used in some embodiments of the present invention.

In other embodiments, L₁, B, L₂ and/or X can be represented by any offormulas (VI)-(VIII):

where (a) R₆ can be optional and can also be independently selected froma substituted, unsubstituted, hetero-, straight-chained, branched,cyclic, saturated or unsaturated aliphatic radical; or a substituted,unsubstituted, or hetero-aromatic radical; (b) R₇ and R₈ can beindependently selected from a substituted, unsubstituted, hetero-,straight-chained, branched, cyclic, saturated or unsaturated aliphaticradical; or a substituted, unsubstituted, or hetero-aromatic radical;(c) R₉ through R₁₂ can be independently selected from a hydrogen; asubstituted, unsubstituted, hetero-, straight-chained, branched, cyclic,saturated or unsaturated aliphatic radical; or a substituted,unsubstituted, or hetero-, aromatic radical; (d) R₁₃ and R₁₄ can beindependently selected from a hydrogen; a substituted, unsubstituted,hetero-, straight-chained, branched, cyclic, saturated or unsaturatedaliphatic radical; and a substituted or unsubstituted aromatic radical.In some embodiments, R₇ is not a substituted, unsubstituted, orhetero-aromatic radical.

In some embodiments using formulas (I), (II) and (VI)-(VIII), m canrange from about 0 to about 50, from about 1 to about 40, from about 2to about 30, from about 3 to about 20, from about 4 to about 10, or anyrange therein; n can range from about 1 to about 1400, from about 10 toabout 800, from about 20 to about 400, or any range therein; p can rangefrom about 4 to about 1400, from about 10 to about 800, from about 20 toabout 400, or any range therein; and z can range from about 10 to about1600, from about 20 to about 1200, from about 30 to about 900, fromabout 50 to about 600, or any range therein; and the sum of n and p andcan range from about 30 to about 1600, from about 50 to about 1200, fromabout 75 to about 900, from about 100 to about 600, or any rangetherein. Generally speaking, the heterogenous nature of the terminalgroups on the hydroxyalkanoates can be altered to make the terminalgroups uniform such that the polymeric reaction products are morepredictable and controllable. In some embodiments, for example, thehydroxyalkanoates can be carboxyl-terminated, hydroxyl-terminated, oramino-terminated.

In some embodiments, the hydroxyalkanoates can be altered to becarboxyl-terminated, for example, by combining the hydroxyalkanoateswith diacids. In other embodiments, the hydroxyalkanoates can be alteredto be hydroxyl-terminated, for example, by combining thehydroxyalkanoates with diols. In other embodiments, thehydroxyalkanoates can be altered to be amino-terminated, for example, bycombining a hydroxyl-terminated hydroxyalkanoate with reactiveamine-containing moieties or reactive moieties that can be converted toamines. In one example, a hydroxyl-terminated hydroxyalkanoate can becombined with aziridine to create an amine-terminated hydroxyalkanoate.In another example, a hydroxyl-terminated hydroxyalkanoate can becombined with a diisocyanate to form an isocyanate-terminatedhydroxyalkanoate that can be combined, for example, with water toproduce an amine-terminated hydroxyalkanoate. In another example, ahydroxyl-terminated hydroxyalkanoate can be combined with tosyl chlorideto form a tosyl-terminated hydroxyalkanoate that can be combined, forexample, with ammonia to displace the tosyl moiety and produce anamino-terminated hydroxyalkanoate. These alterations can be performed onpoly(hydroxyalkanoates) as well, and one of skill in the art can selectthe reaction conditions necessary to obtain the desired reactionproducts.

In some embodiments, the polymers of the present invention can beprepared in the following manner: a poly(hydroxyalkanoate) can becombined with a multi-functional amino acid, a diacid or derivative of adiacid, and an agent. In embodiments where the incorporation of apeptide-type combination is desired, two amino acids can beindependently selected and combined such as, for example, where oneamino acid is bi-functional and the other is multi-functional.

An example of a multi-functional amino acid is a tri-functional aminoacid. Examples of tri-functional amino acids include, but are notlimited to, lysine, tyrosine, arginine, or glutamic acid. Examples ofdiacids include, but are not limited to, the dicarboxylic acids listedabove. Examples of derivatives of diacids include, but are not limitedto, diacid chloride, a dianhydride, or a di-p-nitrophenyl ester. In theevent that a dicarboxylic acid is used, the reaction may be carried outin the presence of 1-ethyl-3(3-dimethylaminopropyl) carbodiimide (EDC)or 1,3-dicyclohexylcarbodiimide (DCC) in a solvent such asdimethylformamide (DMF) or tetrahydrofuran (THF). If a diacid chlorideor di-p-nitrophenyl ester is used, an excess of pyridine ortriethylamine should be present. Examples of other solvents that may beused include, but are not limited to, dimethylacetamide (DMAC),dimethylsulfoxide (DMSO), acetone, and dioxane.

The reaction conditions used in preparing the PEAs copolymer segments,such as those in formulas (VI)-(VIII), should be anhydrous and favoresterification. In some embodiments, the reaction solvents can includetoluene and benzene and should be distilled to remove water. Thereaction can be catalyzed by a strong acid or base such as, for example,p-toluenesulfonic acid (TsOH). In some embodiments, the temperature ofthe reaction ranges from about 25° C. to about 150° C., from about 35°C. to about 100° C., from about 50° C. to about any range therein. Insome embodiments, the reaction times range from about 1 hour to about 24hours, from about 6 hours to about 18 hours, from about 10 hours toabout 14 hours, or any range therein. Any agent described above can beused.

Trifunctional amino acids can be incorporated into the polymer byprotecting the third functionality with a protecting group that is laterremoved. Examples of protecting groups are benzyl esters for the lysinecarboxyl or t-butoxycarbonyl for amino groups such as, for example, theamino group in glutamic acid.

The benzyl ester protecting group may be removed from the lysinecarboxyl by hydrogenolysis with hydrogen gas over a catalyst such as,for example, palladium or platinum on carbon. Examples of suitablesolvents include, but are not limited to, ethanol, methanol,isopropanol, and THF. In some embodiments, the reaction may be conductedunder about 1 atm of hydrogen for about 6 hours to about 24 hours, forabout 8 hours to about 16 hours, for about 10 hours to about 14 hours,or any range therein. After removal of the protecting group, an agentcomprising an amino, a hydroxyl, a thiol, or a combination thereof canbe connected to the carboxyl group. Coupling agents used to connect theagent include, but are not limited to, EDC and DCC. Thionyl chloride orphosphorous pentachloride may be used in a less selective process ofpreparing the acid chloride derivative.

An amine functional compound such as, for example, 4-amino-TEMPO, may beconnected to a polymer containing free carboxyls such as, for example,the lysine-derived carboxyls, by first activating the carboxyls andcoupling the amine in a solvent under agitation. The carboxyls may beactivated with, for example, N-hydroxysuccinimide (NHS) and DCC in asolvent such as, for example, THF or chloroform, which producesN-hydroxysuccinimidyl ester. Examples of the solvent that may be used tocouple the amine to the carboxyls include, but are not limited to, THFand DMF. In some embodiments, the reaction occurs at a temperatureranging from about 5° C. to about 50° C., from about 15° C. to about 35°C., from about 20° C. to about 30° C., or any range therein. In someembodiments, the reaction time ranges from about 0.5 hours to about 24hours, from about 1 hour to about 18 hours, from about 4 hours to about16 hours, from about 6 hours to about 12 hours, or any range therein.

The PEAs can be combined with hydroxyalkanoates to produce copolymersthat are in-chain and/or pendant with the PHA compositions. One purposefor adding PEA functionality is to make a PHA composition that isprohealing, tougher, and that has a higher impact resistance and lowermodulus. Such a PHA composition may be more applicable to particularapplications such as, for example, drug-eluting stents. Another purposefor adding PEA functionality to a PHA composition is to introduce anadditional control over in vivo biodegradation rates and products. Asthe amount of PEA increases in the polymer, the amount of enzymatichydrolysis that occurs in the composition in vivo increases as well,thus providing another mechanism of chain scission that is controllablebased on the design of the composition.

In some embodiments, a family of PHAs can be represented by formula(IX):

wherein the groups R₁ through R₇; and k, m, n, and X are defined above.In one embodiment, R₇ can be a carboxyl terminated alkylene radical inan amino acid, such as, for example lysine.

In other embodiments, a family of PHAs can be represented by formula(X):

wherein the groups R₁ through R₆; and k, m, n, and X are defined above.In one embodiment, R₇ can be a carboxyl terminated alkylene radical inan amino acid, such as, for example lysine.

In another embodiment, a family of PHAs comprising a dipeptide fragmentcan be represented by formula (XI):

wherein the groups R₁ through R₇ and R₁₃; and k, m, n, and X are definedabove. In one embodiment, R₇ can be a carboxyl terminated alkyleneradical in an amino acid, such as, for example lysine.

In another embodiment, a family of PHAs can be represented by formula(XII):

wherein the groups R₁ through R₈; and k, m, n, p, and X are definedabove. In one embodiment, R₇ can be a carboxyl-terminated alkyleneradical in an amino acid, such as, for example lysine.

In another embodiment, a family of PHAs can be represented by formula(XIII):

wherein the groups R₁ through R₈; and k, m, n, and X are defined above.In one embodiment, R₇ can be a carboxyl terminated alkylene radical inan amino acid, such as, for example lysine. In another embodiment, R₆can be independently selected as an alkylene radical such as, forexample, an ethylene radical. The main portion of this polymer is apoly(hydroxyalkanoate diacid)(“PHADA”). Accordingly, formula (XIII) canbe combined, for example, with formulas (VI)-(VIII) to produce a familyof polymers that can include, but is not limited to, formula (XIV):

wherein R₆, R₇, and X are defined above, and in some embodiments, R₇ canbe a carboxyl-terminated alkylene radical in an amino acid, such as, forexample lysine.

In another embodiment, a family of PHAs comprising amino-terminatedhydroxyalkanoates can be represented by formula (XV):

wherein the groups R₁ through R₈; and k, m, n, p and X are definedabove. The group R₁₅ is part of the moiety used to create anamino-terminated hydroxyalkanoate. In some embodiments, R₁₅ can be analkylene, an amide, an acyl or a combination thereof. In otherembodiments, R₁₅ can be an ethylene radical. In one embodiment, R₇ canbe a carboxyl terminated alkylene radical in an amino acid, such as, forexample lysine. In another embodiment, R₆ can be independently selectedas an alkylene radical such as, for example, an ethylene radical.

A variety of moieties, including the agents described above, can beattached pendant and/or in-chain with the PHAs of the present inventionas follows:

I. Agents Attached Pendant to the Polymer

Agents can be attached to any of the polymers taught herein in a varietyof ways. For example, the agents can be connected covalently ornon-covalently such as, for example, by ionic attachment, hydrogenbonding, metal ion coordination, or physical interlinking. In someembodiments, the A, L₁, B, L₂, and/or X can be chemically functionalizedto provide sites for connecting agents as pendant groups to the PHAcompositions. Examples of functional groups that can be used in formingthe connections are described above.

In some embodiments, the functional groups introduced to A, L₁, B, L₂,and/or X include, but are not limited to, carboxylic acids, amines,thiols, alcohols, anhydrides, esters, unsaturated groups and halogens.In other embodiments, metals can be introduced as functional groups forlinking agents to polymers. In other embodiments of the presentinvention, diacids comprising epoxy groups may be included in the PHAsas highly-strained reactive groups that can be used to connect agents tothe polymer. Examples of such PHAs may include, but are not limited to,2,3-epoxysuccinic acid, 3,4-epoxyadipic acid or a diepoxyadipic acid.

Surface treatments can be used to functionalize the polymer surface andinclude, for example, chemical, mechanical, and combined chemical andmechanical treatments, which are known to one of skill in the art.Mechanical surface treatment includes, but is not limited to, abrading,polishing, and applying laser energy to a surface. Laser surfacetreatment includes applying laser energy to heat, oxidize, pyrolyze,activate, or cleave chemical bonds. Chemical surface treatment includes,but is not limited to, etching such as, for example, chromic acidetching; ozonation; iodine treatment; sodium treatment; surfacegrafting; anodizing; thermal, flame, UV, corona discharge, and plasmatreatments; and the use of primers. In some embodiments, medicalarticles may be surface treated after they have been formed, which canreduce problems that may be associated with using functionalized PHAs toform a medical article. In some embodiments, such treatments can be usedto localize the functional groups to predetermined regions on a polymersurface and allow for localization of select agents.

In some embodiments, the surface treatment comprises chromic acidetching to introduce functional groups such as, for example, hydroxyl,carbonyl, carboxylic acid, and —SO₃H groups and form root-like cavitieswhich provide sites for mechanical interlocking. In other embodiments,the surface treatment comprises applying a more aggressive etchingsolution containing, for example, a sodium-naphthalene complex dissolvedin tetrahydrofuran or a sodium-ammonia complex dissolved in ammonia tointroduce unsaturated bonds, carbonyl groups, and carboxyl groups. Inother embodiments, the surface treatment comprises iodine treatment toalter the crystallinity of the polymer surface from an alpha form (wherethe N—H groups lie parallel to the surface) to a beta form (where theN—H groups stand perpendicular to the surface). In other embodiments,the surface treatment comprises application of a primer, which istypically a multifunctional chemical, to act as a chemical bridgebetween the polymer and an agent.

In some embodiments, the surface treatment comprises surface grafting achemical to a polymeric surface to provide functional groups forattachment of an agent such as, for example, exposing a poly(ethylene)to gamma radiation in the presence of a vinyl acetate monomer tochemically graft the vinyl acetate monomer on the poly(ethylene)surface. In other embodiments, the surface treatment comprises plasmatreatment with ions of a gas such as, for example, Ar, He, N₂, O₂, air,and NH₃ to introduce functional groups such as, for example, carboxylicor amino groups. In other embodiments, the surface treatment comprises acorona discharge, usually in the presence of air and at atmosphericpressure, to introduce functional groups such as, for example, carbonyl,hydroxyl, hydroperoxide, aldehyde, ether, ester, and carboxylic acidgroups, as well as unsaturated bonds.

In some embodiments, the surface treatment comprises flame treatment tooxidize the polymer surface and introduce functional groups such as, forexample, hydroxyl, carbonyl, carboxyl, and amide groups through a freeradical mechanism. In other embodiments, the surface treatment comprisesthermally treating a polymeric surface to a blast of hot air(approximately 500° C.) to create functional groups such as, forexample, carbonyl, carboxyl, amide, and hydroperoxide groups through afree radical mechanism. In other embodiments, the surface treatmentcomprises applying ultraviolet (UV) radiation with high intensity UVlight of a predetermined wavelength to create functional groups, wherethe process may use, for example, a wavelength of 184 nm to crosslinkthe surface of a polyethylene or a wavelength of 253.7 nm to avoidcross-linking and induce hydrogen bonding. In other embodiments, thesurface treatment comprises abrading or polishing the polymer surface inthe presence of an agent to create free radicals that react directlywith the agent.

The selection of functional groups for connecting an agent to a polymerwill affect the ability of the agent to release from the polymer invivo. In formula (X), for example, L₂ is an ester, which may beundesirable in some embodiments. As illustrated and described below, thecareful selection of L₂ can help alleviate safety and regulatory issuesthat may arise from the creation of derivatives of X duringbiodegradation of the polymers.

Examples of L₂ include, but are not limited to, amides, ureas,urethanes, esters, semicarbazones, imines, oximes, anhydrides, ketals,acetals, orthoesters, disulfides, and all-aromatic carbonates. In someembodiments, L₂ can be an ester, an anhydride, a ketal, an acetal, anorthoester, or an all-aromatic carbonates. In some embodiments, L₂ canbe an anhydride, a ketal, an acetal, an orthoester or an all-aromaticcarbonate. In some embodiments, L₂ can be a ketal, an acetal, anorthoester or an all-aromatic carbonate. In some embodiments, L₂ can bean acetal, an orthoester or an all-aromatic carbonate. In someembodiments, L₂ can be an orthoester or an all-aromatic carbonate. Insome embodiments, L₂ can be an all-aromatic carbonate, which includeslinkages comprising moieties represented by formula (XVI):

wherein R is optional and can be independently selected from, forexample, a substituted, unsubstituted, hetero-, straight-chained,branched, cyclic, saturated and unsaturated aliphatic radicals;substituted and unsubstituted aromatic radicals; and combinationsthereof. The subscript n is an integer.

In some embodiments, the PHA is represented by formula (XVII):

wherein R₁ through R₄, k, m, and n are defined above; and the number ofethylene oxide repeating units ranges from about 1 to about 100, fromabout 2 to about 80; from about 3 to about 70, from about 4 to about 60,from about 2 to about 20, from about 3 to about 30, from about 4 toabout 40, from about 5 to about 50, and any range therein.

In formula (XVII), the diacid is sebacic acid, the amino acid is lysine,and the agent is mPEG. The mPEG is connected to the B-moiety through anamide linkage, which is a stable linkage relative to the stability ofthe remainder of the polymer. It should be appreciated that any PEGderivative may be used.

Adding PEO functionality to a PHA composition modifies the compositionby, for example, increasing water uptake, which provides a plasticizingeffect and makes the polymer more flexible to increase toughness. Anincrease in water uptake can also increase the hydrolysis rate andthereby provide an additional control over biodegradation and drugrelease rate. The PEG component may leach from a blend or mixture of PEGand PHA at a rate faster than desired due to the relative hydrophilicityof the PEG phase in the blend or mixture. Copolymerization of a PEOfunctionality with the PHA compositions will prevent such leaching bycircumventing a phase separation that otherwise occurs in blends ofhydrophobic and hydrophilic materials. The copolymers will allow for anincreased loading concentration of the hydrophilic PEG moiety andsustain any improvements in mechanical and biobeneficial properties thatare realized by the addition of the PEG.

In some embodiments, the PHA is represented by formula (XVIII):

wherein R₁ through R₄, k, m, and n are defined above.

In formula (XVIII), the diacid is sebacic acid, the amino acid islysine, and the agent is4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO). The4-amino-TEMPO is connected to the B-moiety through an amide linkage,which may remain intact during biodegradation of the polymer resultingin attachment of additional molecules to the 4-amino-TEMPO that werederived from degradation of the polymer at the ester linkages. As aresult, such a released agent would be a derivative of 4-amino-TEMPOrather than 4-amino-TEMPO and could cause regulatory concerns.

In some embodiments, the PHA is represented by formula (XIX):

wherein R₁ through R₄, k, m, and n are defined above.

In formula (XIX), the diacid is sebacic acid, the amino acid is lysine,and the agent is4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl(4-hydroxy-TEMPO). The4-hydroxy-TEMPO is connected to the B-moiety through an ester linkage,which is more labile than an amide linkage and allows for release of theagent from the polymer. The cleavage of the L₂ ester competes with thecleavage of the PEA esters and may result in attachment of additionalmolecules to the 4-hydroxy-TEMPO that were derived from degradation ofthe polymer at ester linkages.

In some embodiments, the PHA is represented by formula (XX):

wherein R₁ through R₄, k, m, and n are defined above.

In formula (XX), the diol is butane-1,6-diol, the diacid is sebacicacid, the amino acid is lysine, and the agent is4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl(4-carboxy-TEMPO). The4-carboxy-TEMPO is connected to the B-moiety through an anhydridelinkage, which is more labile than an ester linkage and, thus, may allowfor release of the agent without attachment of additional moleculesderived from biodegradation of the polymer at ester linkages.

In some embodiments, the PHA is represented by formula (XXI):

wherein R₁ through R₄, k, m, and n, and the number of ethylene oxiderepeating units are defined above.

In formula (XXI) the diacid is sebacic acid, one amino acid is leucine,the other amino acid is lysine, X is PEG and L₂ is an amide, which isstable relative to the stability of the remainder of the polymer. Itshould be appreciated that any PEG derivative such as, for example, mPEGcan also be used.

There are a variety of commercially available PEG molecular weights andderivatives that are designed for specific applications. In someembodiments, the PEG can be functionalized to allow attachment of thePEG to any functional group taught herein such as, for example, amine,thiol, hydroxyl and carboxyl functional groups. In these embodiments,the attachment of the PEG can be covalent, non-covalent, biodegradableor non-biodegradable. The PEGs may also be used as a point of attachmentfor carrying and/or delivering any other agents taught herein. In otherembodiments, the PEG can be combined with the PHA compositions in theform of a crosslinked hydrogel for the covalent attachment, non-covalentattachment, and the modulation of the delivery rates of agents. In otherembodiments, the PEGs have a molecular weight of 30,000 Daltons or less,or can be biodegraded to fragments that have a molecular weight of30,000 Daltons or less to ensure renal clearance from a subject.

In some embodiments, a PHA is represented by formula (XXII):

wherein R₁ through R₄, k, m, and n are defined above.

In formula (XXII), the diacid is sebacic acid, the amino acid isleucine, X is estradiol and L₂ is an orthoester known as3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane (DETOSU), whichis more labile than an ester. To make the polymer of formula (XXII), oneequivalent of glycerol can be combined with two equivalents of leucineto obtain an amino-terminated polymeric subunit. Next, a PHA can becombined with sebacic acid and the amino-terminated polymeric subunit toobtain a hydroxy-functional PHA. Estradiol can then be combined with3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane (DETOSU) to forman estradiol-DETOSU moiety. The hydroxy-functional PHA can be reactedwith the estradiol-DETOSU to form the PEA-agent combination.

A polymeric agent such as, for example, a glycosaminoglycan can beconnected to a PHA as a graft-copolymer. In some embodiments, theglycosaminoglycan is aldehyde-terminated and is connected to the PHA ata primary amine. A PHA with pendant amino groups on the polymer backbonemay be produced by a method that comprises polymerizing a PHA with anacid-terminated unit formed by reacting di-p-nitrophenyl sebacate andε-carbobenzoxy-L-lysine in a suitable solvent such as, for example, DMFor THF. The PHA can be combined with the acid-terminated unit using acarbodiimide.

In the coupling of a glycosaminoglycan to a PHA, a mixed population ofsebacic acid and sebacic acid coupled to protected lysines can beblended and reacted with the PHA to form diblock copolymers of apredetermined design. The temperature of the reaction ranges from about25° C. to about 150° C., from about 50° C. to about 125° C., from about80° C. to about 100° C., or any range therein. The reaction occurs for atime ranging from about 1 hour to about 24 hours, from about 6 hours toabout 18 hours, from about 10 hours to about 14 hours, or any rangetherein. The carbobenzoxy protecting group can be removed withhydrogenolysis over a palladium-on-carbon catalyst using the methoddescribed above. A glycosaminoglycan such as, for example, an aldehydeterminated heparin, can be connected to the PHA by reductive aminationusing sodium cyanoborohydride (NaCNBH₃) and a DMF/water solvent. In someembodiments, the glycosaminoglycan can be hyaluronic acid or aderivative thereof.

A PEA can also be connected to a PHA as a graft copolymer in a similarmanner. In some embodiments, the PHA can have a backbone that containsall hydroxyalkanoates. In other embodiments, the backbone of the polymercan be a copolymer of PHA and PEA. In other embodiments, the backbone ofthe polymer can be a copolymer of PHA and PEG. In other embodiments, thepolymer can be a copolymer of PHA and any other polymer taught herein.

In some embodiments, the number average molecular weight of the PEA in aPEA-PHA graft copolymer can range from about 1000 to about 60,000, fromabout 1000 to about 50,000, from about 1000 to about 40,000, from about1500 to about 35,000, from about 1500 to about 30,000, from about 1750to about 25,000, from about 2000 to about 20,000, from about 2,000 toabout 15,000, from about 2000 to about 10,000, or any range therein.

II. Agent as a Copolymer

The methods of the present invention can be designed to produce avariety of copolymers such as graft copolymers, an AB copolymer, an ABAcopolymer, or an ABABAB . . . multi-block copolymer by activating eitherone or both ends of the agent polymer and the polyester. The AB-typecopolymers result when the two polymers only have a single active end.Copolymers of the ABA-type result where one polymer has one active endand the other polymer has two active ends. Copolymers of the ABABAB . .. -type result where both polymers have two active ends.

A polymeric agent can be connected to a PHA as a copolymer and can beany agent taught herein. In some embodiments, the agents include, butare not limited to, poly(alkylene glycols) such as, for example,poly(ethylene glycol) and poly(propylene glycol); phosphorylcholine;poly(N-vinyl pyrrolidone); poly(ethylene oxide); poly(acrylamide methylpropane sulfonic acid); poly(2-hydroxyethyl methacrylate),poly(3-hydroxypropyl methacrylamide), poly(styrene sulfonate);saccharides such as, for example, carboxymethylcellulose; sulfonatedpolysaccharides such as, for example, sulfonated dextran; sulfatedpolysaccharides such as, for example, sulfated dextran and dermatansulfate; and any derivatives, analogs, homologues, congeners, salts,copolymers and combinations thereof. In other embodiments, the agentscan include, but are not limited to, glycosaminoglycans such as, forexample, hyaluronic acid, heparin, hirudin, dermatan sulfate,chondroitin sulfate; chitin; chitosan; and any derivatives, analogs,homologues, congeners, salts, copolymers and combinations thereof.

In other embodiments, the agents can be prohealing such as, for example,poly(ester amides), elastin, silk-elastin, collagen; chondroitinsulfate; peptide sequences such as, for example, atrial natriureticpeptide (ANP), and those comprising Arg-Gly-Asp (RGD); and anyderivatives, analogs, homologues, congeners, salts, copolymers andcombinations thereof. In other embodiments, the agents can benon-thrombotics such as, for example, thrombomodulin; antimicrobialssuch as, for example, the organosilanes; and any derivatives, analogs,homologues, congeners, salts, copolymers and combinations thereof.

1. PHAs Comprising Glycosaminoglycans such as Heparin or Hyaluronic Acid

A graft copolymer of a PHA and a glycosaminoglycan such as heparin orhyaluronic acid, or a block copolymer of a PHA with an endblock of aglycosaminoglycan such as heparin or hyaluronic acid can be prepared. Insome embodiments, these copolymers can be prepared by combining an aminofunctional or an amino-terminated PHA with an aldehyde-derivatizedheparin. An example of a aldehyde-derivatized heparin is represented byformula (XXIII):

wherein p is an integer not equal to 0.

The aldehyde-terminated heparin can be combined, for example, with anamino functional PHA in DMF solvent at 40 C, and dissolved. NaCNBH₃ isadded to reduce the Schiff base formed and the solution is stirred for24-48 hours to produce a PHA-heparin copolymer structure, either graftor block, depending on the placement of the heparin.

An ABA block-copolymer of PHA and heparin with PHA as the B block, canbe prepared by combining a carboxyl-terminated PHA with analdehyde-terminated heparin. The carboxyl-terminated PHA is firstactivated with, for example, EDC or DCC and then combined with a largeexcess of adipic dihydrazide to prepare an amino-functionalized PHA. Theheparin is then coupled to the PHA by reductive amination as describedabove. Alternatively, an aldehyde-terminated heparin can be treated withammonia or n-butylamine in the presence of a reducing agent such as, forexample, sodium borohydride (NaBH₄), potassium borohydride (KBH₄), orsodium cyanoborohydride (NaCNBH₃). The carboxyl-terminated PHA can beactivated with, for example, EDC or DCC, and combined with theamino-functional heparin.

It should be appreciated that, in some embodiments of the presentinvention, the agent may be any biobeneficial agent that can enhance thebiocompatibility or non-fouling properties of a PHA polymer, as well asmodify a physical/mechanical property of the polymer. For example,hyaluronic acid can be a polymeric agent used to form a PHA-hyaluronicacid copolymer, such as a graft copolymer or an end-block copolymer.Hyaluronic acid has free carboxyl groups, and an aldehyde-derivatizedhyaluronic acid can be made, for example, by oxidizing hyaluronic acidwith nitrous acid or periodate. The aldehyde-derivatized hyaluronic acidcan then be combined with a polyester as described above.

A PHA that is multifunctional, such as a PHA that is bothcarboxyl-terminated and hydroxyl-terminated, for example, can beanalyzed using standard analytical techniques to determine a ratio ofcarboxyl groups to hydroxyl groups. The same is true of a PHAcomposition that also contains amino functionality. Knowing the ratio offunctionalities will allow one skilled in the art to decide whether toconnect the polymeric agent to the hydroxyl ends, the amino ends, or thecarboxyl ends of a PHA composition. A skilled artisan can protect groupson the PHA such as amino groups, for example, with benzyl chloroformateto reduce undesirable side conjugation when combining acarboxyl-terminated PHA with an aldehyde derivative that was convertedto a hydrazide of a glycosaminoglycan.

PHAs Containing Poly(Ethylene Glycol) Blocks

A block copolymer of PHA and PEG can be prepared using a variety oftechniques. Some purposes for adding PEO functionality to a PHA arediscussed above. In one embodiment, a PHA with a hydroxyl and a carboxylendgroup can be combined with a PEG possessing a hydroxyl and a carboxylendgroup (Nektar Corp.) in the presence of, for example, EDC or DCC toform the following structure represented by formula (XXIV):

wherein n, r, and z are integers not equal to 0; and n and z aredescribed above.

In another embodiment, an amino-terminated PHA can be combined with adi-carboxyl-terminated PEG (Nektar Corp.) in the presence of, forexample, EDC or DCC. In another embodiment, either a succinimidylderivative of mPEG (Nektar Corp.) or an isocyanate-terminated mPEG(Nektar Corp.) can be reacted with an amino-terminated PHA underconditions known to one of skill in the art. In another embodiment, thecarboxyl group of a carboxyl-terminated PHA can be activated with, forexample, EDC or DCC and combined with an amino-terminated mPEG (NektarCorp.). In another embodiment, an amino-terminated mPEG can be combinedwith a high molecular weight PHA in the presence of a base catalystthrough amination of ester groups. In another embodiment, anamino-terminated PHA can be combined with ethylene oxide in a livingpolymerization reaction that forms a PEG block, and which is anunterminated, anionic polymerization kept alive and controlled bymaintaining a pure system. A living polymerization reaction can bestopped through addition of a terminating agent such as, for example,water.

The PHA-PEG copolymer shown above is an AB-block copolymer. In someembodiments, r can range from about 1 to about 2500, from about 10 toabout 2000; from about 20 to about 1500, from about 50 to about 1500,from about 100 to about 2300, from about 1000 to about 2300, and anyrange therein; n and p can independently range from about 1 to about1500, from about 5 to about 1000; from about 10 to about 500, from about20 to about 500, from about 30 to about 1300, from about 50 to about1500, and any range therein.

In another embodiment, an amino-terminated PHA can be combined with acarboxyl-terminated PEG (Nektar Corp.) in the presence of, for example,EDC or DCC. In another embodiment, either a succinimidyl derivative ofmPEG (Nektar Corp.) or an isocyanate-terminated mPEG (Nektar Corp.) canbe reacted with a hydroxyl, amino, or sulphydryl functional PHA underconditions known to those of skill in the art. In another embodiment,the carboxyl group of a carboxyl-terminated PHA can be activated with,for example, EDC or DCC and combined with an amino-terminated PEG(Nektar Corp.) In another embodiment, an amino-terminated PEG can becombined with a high molecular weight PHA in the presence of an acid orbase catalyst through amination of ester groups in a high molecularweight PHA. In another embodiment, an amino-terminated PHA can becombined with ethylene oxide in a living polymerization reaction, whichis an unterminated, anionic polymerization kept alive and controlled bymaintaining a pure system. A living polymerization reaction can bekilled through addition of a terminating agent such as, for example,water.

Forming a Coating

In some embodiments of the invention, the compositions are in the formof coatings for medical devices such as, for example, aballoon-expandable stent or a self-expanding stent. There are manycoating configurations within the scope of the present invention, andeach configuration can include any number and combination of layers. Insome embodiments, the coatings of the present invention can comprise oneor a combination of the following four types of layers:

(a) an agent layer, which may comprise a polymer and an agent or,alternatively, a polymer free agent;

(b) an optional primer layer, which may improve adhesion of subsequentlayers on the implantable substrate or on a previously formed layer;

(c) an optional topcoat layer, which may serve as a way of controllingthe rate of release of an agent; and

(d) an optional biocompatible finishing layer, which may improve thebiocompatibility of the coating.

In one embodiment, the agent layer can be applied directly to at least apart of an implantable substrate as a pure agent to serve as a reservoirfor at least one bioactive agent. In another embodiment, the agent canbe combined with a biodegradable polymer as a matrix, wherein agent mayor may not be bonded to the polymer. In another embodiment, the optionalprimer layer can be applied between the implantable substrate and theagent layer to improve adhesion of the agent layer to the implantablesubstrate and can optionally comprise an agent. In another embodiment, apure agent layer can be sandwiched between layers comprisingbiodegradable polymer. In another embodiment, the optional topcoat layercan be applied over at least a portion of the agent layer to serve as amembrane to control the rate of release of the bioactive agent and canoptionally comprise agent. In another embodiment, the biocompatiblefinishing layer can also be applied to increase the biocompatibility ofthe coating by, for example, increasing acute hemocompatibility and canalso comprise an agent.

The inventive compositions can be used for one or any combination oflayers. In some embodiments, any of the other polymers taught herein canbe used as one of the layers or can be blended or crosslinked with thePHA embodiments. Each layer can be applied to an implantable substrateby any method including, but not limited to, dipping, spraying, pouring,brushing, spin-coating, roller coating, meniscus coating, powdercoating, inkjet-type application or a combination thereof. In oneexample, each of the layers can be formed on a stent by dissolving oneor more biodegradable polymers, optionally with a non-biodegradablepolymer, in one or more solvents and either (i) spraying the solution onthe stent or (ii) dipping the stent in the solution. In this example, adry coating of biodegradable polymer may be formed on the stent when thesolvent evaporates.

The formation of each layer may involve use of a casting solvent. Acasting solvent is a liquid medium within which a polymer can besolubilized to form a solution that may be applied as a coating on asubstrate. The casting solvent must be selected to avoid adverselyaffecting an underlying material such as, for example, an underlyingprimer layer or a bare stent structure. In one example, a material usedto form the primer layer is soluble in a highly polar casting solventbut is reasonably insoluble in a low polarity casting solvent. Amaterial is “reasonably insoluble” in a solvent when the material doesnot solubilize to an extent great enough to significantly affect theperformance of the resulting product, meaning that the product can stillbe used for its intended purpose. In this example, an overlying agentlayer that is soluble in a low polarity casting solvent can be appliedto the underlying primer layer without disrupting the structure ofprimer layer.

The casting solvent may be chosen based on several criteria including,for example, its polarity, ability to hydrogen bond, molecular size,volatility, biocompatibility, reactivity and purity. Other physicalcharacteristics of the casting solvent may also be taken into accountincluding the solubility limit of the polymer in the casting solvent,the presence of oxygen and other gases in the casting solvent, theviscosity and vapor pressure of the combined casting solvent andpolymer, the ability of the casting solvent to diffuse through anunderlying material, and the thermal stability of the casting solvent.

One of skill in the art has access to scientific literature and dataregarding the solubility of a wide variety of polymers. Furthermore, oneof skill in the art will appreciate that the choice of casting solventmay begin empirically by calculating the Gibb's free energy ofdissolution using available thermodynamic data. Such calculations allowfor a preliminary selection of potential solvents to test in alaboratory. It is recognized that process conditions can affect thechemical structure of the underlying materials and, thus, affect theirsolubility in a casting solvent. It is also recognized that the kineticsof dissolution are a factor to consider when selecting a castingsolvent, because a slow dissolution of an underlying material, forexample, may not affect the performance characteristics of a productwhere the product is produced relatively quickly.

Exemplary casting solvents for use in the present invention include, butare not limited to, DMAC, DMF, THF, cyclohexanone, xylene, toluene,acetone, i-propanol, methyl ethyl ketone, propylene glycol monomethylether, methyl butyl ketone, ethyl acetate, n-butyl acetate, and dioxane.Solvent mixtures can be used as well. Representative examples of themixtures include, but are not limited to, DMAC and methanol (50:50 w/w);water, i-propanol, and DMAC (10:3:87 w/w); i-propanol and DMAC (80:20,50:50, or 20:80 w/w); acetone and cyclohexanone (80:20, 50:50, or 20:80w/w); acetone and xylene (50:50 w/w); acetone, xylene and FLUX REMOVERAMS® (93.7% 3,3-dichloro-1,1,1,2,2-pentafluoropropane and1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance is methanolwith trace amounts of nitromethane; Tech Spray, Inc.) (10:40:50 w/w);and 1,1,2-trichloroethane and chloroform (80:20 w/w).

It should be appreciated that a process of forming a medical article orcoating can include additional process steps such as, for example, theuse of energy such as heat, electromagnetic radiation, electron beam,ion or charged particle beam, neutral-atom beam, and chemical energy.The process of drying can be accelerated by using higher temperatures.

A medical article or coating can also be annealed to enhance themechanical properties of the composition. Annealing can be used to helpreduce part stress and can provide an extra measure of safety inapplications such as complex medical devices, where stress-crackingfailures can be critical. The annealing can occur at a temperature thatranges from about 30° C. to about 200° C., from about 35° C. to about190° C., from about 40° C. to about 180° C., from about 45° C. to about175° C., or any range therein. The annealing time can range from about 1second to about 60 seconds, from about 1 minute to about 60 minutes,from about 2 minute to about 45 minutes, from about 3 minute to about 30minutes, from about 5 minute to about 20 minutes, or any range therein.The annealing can also occur by cycling heating with cooling, whereinthe total time taken for heating and cooling is the annealing cycletime.

The following examples are provided to further illustrate embodiments ofthe present invention.

Example 1 Preparation of Hydroxyl-Terminated, Carboxyl-Terminated andAmino-Terminated PHAs

A hydroxyl-terminated PHA can be prepared by several routes. In oneroute, a hydroxyl-acid compound such as lactic acid or ε-hydroxycaproicacid can be polymerized using acid catalysis, and dehydratingconditions, to produce a low molecular weight PHA with a hydroxyl and acarboxyl endgroup. In the presence of coupling agents such as DCC, anamine-hydroxyl compound such as ethanolamine can be coupled to thecarboxyl endgroup resulting in a hydroxyl endgroup. Using the same PHAwith a hydroxyl and carboxyl endgroups, the carboxyl endgroup can beselectively reduced to hydroxyl with borane. In another route, ringopening polymerization can be performed using a dihydric initiator, suchas a diol, and a cyclic lactone.

1,6-hexanediol (14.77 gm (0.125 mole) can be added to a 250 ml,three-necked flask equipped with magnetic stirring, vacuum, and argonpurge. Using an oil bath, the diol can be heated to 60° C. and stirredunder vacuum for two hours to remove water. The flask can be purged withargon, D,L-lactide (108.0 g, 0.75 mole) can be added, and the vacuum canbe applied with stirring for another 30 minutes. After purging withargon, the flask can be heated to 140° C., and polymerization can beinitiated by addition of 10.8 ml of a 5% (w/w) solution of stannousoctoate in dry toluene. After stirring for 24 hours, the reactionsolution can be cooled and poured into 500 ml of cold methanol toprecipitate the polymer. The polymer can be washed withmethanol/petroleum ether and dried under vacuum.

A carboxyl-terminated PHA can be prepared by several routes. In oneroute, a hydroxyl-acid compound such as lactic acid or ε-hydroxycaproicacid can be polymerized using acid catalysis and dehydrating conditionsto produce a low molecular weight PHA with a hydroxyl and a carboxylendgroup. This compound can be reacted with succinic anhydride toconvert the hydroxyl group to a carboxyl group. Otherwise, a PHA can bemade by ring opening polymerization using a diol initiator which has twohydroxyl endgroups.

The poly(D,L-lactide) polymer from above (25 g, 0.0255 mole) andsuccinic anhydride (5.1 g, 0.051 mole) can be dissolved in 100 ml ofanhydrous chloroform. The solution can be stirred at 40° C. overnight.The reaction solution can be cooled and poured into 1000 ml of coldmethanol to precipitate the polymer. The polymer can be washed withmethanol/petroleum ether and dried under vacuum.1,3-dicyclohexylcarbodiimide (DCC) (0.103 g, 5×10⁻⁴ mole) and4-dimethylaminopyridine (0.0012 g, 1×10⁻⁵ mole) can be added. Afterstirring at room temperature for 24 hours, the reaction solution can becentrifuged to precipitate the dicyclohexylurea formed, and thesupernatant solution can be poured into 150 ml of cold methanol toprecipitate the polymer. After collection by filtration, the polymer canbe washed with methanol/petroleum ether and dried under vacuum.

An amino-terminated PHA can be prepared by several routes. In one route,a hydroxyl functional PHA can be reacted with aziridine. In anotherroute, the hydroxyl functional PHA can be first derivatized with tosylchloride, tresyl chloride, or trifluoromethanesulfonyl choride. Theresulting derivative can then be reacted with an excess of an amine suchas ammonia, ethanediamine, 1,4-butanediamne, or 1,5-pentanediamine. Inyet another route, the hydroxyl functional PHA can be reacted with anexcess of diisocyanate, which can then be hydrolyzed with water to yieldthe amino-terminated PHA.

The poly(D,L-lactide) polymer from above (25 g, 0.0255 mole),hexamethylene diisocyanate (13.89 g, 0.102 mole), and stannous octoate(0.4 gm, 0.001 mole) can be dissolved in 200 ml of anhydrous chloroform.The solution can be stirred at 40° C. for 2 hours. The reaction solutioncan be cooled and poured with agitation into 1000 ml of deionized water.After stirring at ambient temperature for 2 hours, the chloroform layercan be isolated and added to 1000 ml of methanol. The precipitatedpolymer can be washed with methanol/petroleum ether and dried undervacuum. This procedure yields a di-amino-terminated poly(D,L-lactide).

Example 2 Preparation of the PHA of Formula (XVII)

Three components are needed to prepare this polymer: a PHA with carboxyland hydroxyl endgroups, a benzyl ester protected lysine, and sebacoylchloride.

Preparation of Poly(Caprolactone) with Carboxyl and Hydroxyl Endgroups

ε-hydroxycaproic acid (100 gm, 0.757 mole), p-toluenesulfonic acidmonohydrate (14.39 gm, 0.0757 mole), and toluene (350 ml) can be addedto a 1000 ml, three necked flask equipped with argon purge, mechanicalstirrer, oil bath, and Dean-Stark trap with reflux condenser. Thesolution can be heated to reflux, and the reaction can be run until12.26 ml of water is collected in the Dean-Stark trap, indicating apolymer of approximately 1158 Daltons molecular weight. After cooling,the solution can be added to deionized water (500 ml) and stirred for 20minutes. The toluene layer can be isolated and extracted with 1 N sodiumbicarbonate (400 ml), followed by two portions of deionized water (400ml). After adding the toluene phase to methanol (1000 ml), the polymercan be isolated by filtration and dried for 48 hours under a vacuum of 1torr at 40° C.

Preparation of poly(caprolactone)-N-L-lysine benzyl ester monotosylate

The poly(caprolactone) polymer from above (50 gm, 0.043 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (25.07 gm, 0.043mole), triethylamine (4.35 gm, 0.043 mole), and tetrahydrofuran (THF)(200 ml) can be added to a 500 ml, 3-necked flask equipped with argonpurge and mechanical stirrer. After dissolution, DCC (8.87 gm, 0.043mole) ican be added, and the solution can be stirred overnight atambient temperature. The solution can be filtered to remove thedicyclohexylurea formed and slowly added to methanol (1000 ml) withstirring to precipitate the polymer. The polymer can be redissolved inchloroform (200 ml), precipitated in isopropyl alcohol (1000 ml), anddried under a vacuum of about 1 torr at about 40° C. for about 48 hours.

Preparation of co-poly[N,O-adipoyl-L-lysine benzylester-polycaprolactone]

Poly(caprolactone)-N-L-lysine benzyl ester monotosylate (50 gm, 0.0323mole), triethylamine (10.79 gm, 0.107 mole), and anhydrous 2-butanone(125 ml) can be added to a 500 ml, 3-necked flask equipped withmechanical stirrer, argon inlet, 50 ml addition funnel, and ice bath.After dissolution, a solution of adipoyl chloride (5.91 gm, 0.0323 mole)in anhydrous 2-butanone (25 ml) can be added with stirring for over 30minutes while maintaining the reaction at 0° C. The reaction can beallowed to warm to room temperature and stirred for 4 more hours. Thesolution can be added to a deionized water (1000 ml) with stirring toprecipitate the polymer. The polymer can be redissolved in THF (200 ml)and reprecipitated in deionized water (1000 ml) with stirring. Thepolymer can be redissolved in chloroform (500 ml) and filtered through adry disc apparatus (Horizon Technologies, Atkinson, N.H.) to removewater. The solution can be concentrated by rotary evaporation, pouredinto Teflon trays, and dried at about 40° C. under a vacuum of about 1torr for about 48 hours.

Hydrogenolysis of co-poly[N,O-adipoyl-L-lysine benzylester-polycaprolactone]

Palladium powder (5 gm, 0.047 mole) can be added to a 1000 ml flaskequipped with an argon inlet, vacuum line, and hydrogen gas inlet,wherein vacuum can be applied for 30 minutes. After purging with argon,THF can be added (500 ml) and hydrogen bubbled through the solution for30 minutes. Co-poly[N,O-adipoyl-L-lysine benzyl ester-polycaprolactone](50 gm) can be added under argon, dissolved, and the solution stirredwith a steady bubbling of hydrogen through the solution for 12 hours.The palladium can be removed by filtration, and the THF solution can beadded dropwise with stirring to deionized water (1500 ml). Afterisolation by filtration, the polymer can be redissolved in chloroform(500 ml), and filtered through a dry disc apparatus (HorizonTechnologies, Atkinson, N.H.) to remove water. The solution can beconcentrated by rotary evaporation, poured into Teflon trays, and driedat about 40° C. under a vacuum of about 1 torr for about 48 hours.

Coupling of mPEG-NH₂ to co-poly[N,O-adipoyl-L-lysine-polycaprolactone]

Co-poly[N,O-adipoyl-L-lysine-polycaprolactone] (10 gm, 0.00689 molecarboxyl), N-hydroxysuccinimide (0.872 gm, 0.00758 mole), and anhydrousTHF (150 ml) can be added to a 250 ml, 3-necked flask equipped withargon purge and magnetic stirrer. After dissolution,dicylohexylcarbodiimide (1.56 gm, 0.00758 mole) can be added as asolution in anhydrous THF (10 ml). The solution can be stirred atambient temperature for 16 hours, and the precipitated dicyclohexylureacan be removed by vacuum filtration. In a separate 250 ml, 3-neckedflask, the solution can be stirred under argon whilemethoxy-poly(ethylene glycol)-amine MW=559.7 (3.856 gm, 0.00689 mole,Quanta Biodesign, Powell, Ohio) can be added. After stirring at ambienttemperature for 18 hours, the solution can be added dropwise todeionized water (600 ml). After isolation by filtration, the polymer canbe redissolved in chloroform (100 ml) and filtered through a dry discapparatus (Horizon Technologies, Atkinson, N.H.) to remove water. Thesolution can be concentrated by rotary evaporation, poured into Teflontrays, and dried at about 40° under a vacuum of about 1 torr for about48 hours. This procedure yields a polymer of formula XVII with a pendantmPEG group having a 559 Dalton molecular weight and a weight fraction ofmPEG in the polymer of about 28%.

Example 3 Preparation of the PHA of Formula (XIX)

This preparation begins with theco-poly[N,O-adipoyl-L-lysine-polycaprolactone] possessing a freecarboxyl from Example 2. Co-poly[N,O-adipoyl-L-lysine-polycaprolactone](10 gm, 0.00689 moles carboxyl groups),4-hydroxyl-2,2,6,6-tetramethylpiperidinyl-1-oxyl (1.19 gm, 0.00689 mole)and anhydrous THF (90 ml) can be added to a 3-necked, 250 ml flaskequipped with magnetic stirrer, argon inlet, ice bath, and 25 mladdition funnel. After dissolution, dicyclohexylcarbodiimide (1.56 gm,0.00758 mole) can be added, and the solution can be stirred under argonat ambient temperature for 24 hours. After filtration to remove thedicyclohexylurea, the polymer can be precipitated by slow addition toisopropylacetate (500 ml). The remaining solvent can be removed bydrying at about 40° under a vacuum of about 1 torr for about 48 hours toyield a polymer of formula (XIX).

Example 4 Preparation of the PHA of Formula (XX)

This preparation begins with theco-poly[N,O-adipoyl-L-lysine-polycaprolactone] possessing a freecarboxyl from Example 2. Co-poly[N,O-adipoyl-L-lysine-polycaprolactone](10 gm, 0.00689 moles carboxyl groups), and anhydrous THF (90 ml) can beadded to a 3-necked, 250 ml flask equipped with magnetic stirrer, argoninlet, ice bath, and 25 ml addition funnel. After dissolution, asolution of thionyl chloride (0.82 gm, 0.00689 mole) in anhydrous THF(10 ml) can be added dropwise over 30 minutes while argon is bubbledthrough the solution. After stirring for 30 more minutes at 0° C.,poly(4-vinylpyridine) (2.17 gm Aldrich, Milwaukee, Wis.) can be added,followed by a solution of4-carboxyl-2,2,6,6-tetramethylpiperidinyl-1-oxyl (1.38 gm, 0.00689 mole)and anhydrous THF (10 ml) that can be added dropwise over thirtyminutes. The solution can be allowed to warm to room temperature andstirred for another hour with a constant purge of argon through thesolution. The solution can be filtered to remove the acid scavenger, andthe polymer can be precipitated by slow addition to anhydrousisopropylacetate (500 ml). The remaining solvent can be removed bydrying at about 40° under a vacuum of about 1 torr for about 48 hours toyield a polymer of formula (XX).

Example 5 Preparation of the PHA of Formula (XXII)

Preparation of this polymer requires synthesis of abis-[L-leucine]-1,3-propylene diester-2-one block monomer.

Method of preparing bis-[L-leucine]-1,3-diester-2-propanone

L-leucine (32.80 gm, 0.25 mole), p-toluenesulfonic acid (104.6 gm, 0.55mole), 1,3-dihydroxy acetone dimer (22.53 gm, 0.125 mole), and 200 ml ofbenzene are added to a 3-necked, 1 liter flask. The solution can beheated at 80 C for 8 hours, and condensate can be collected in a DeanStark trap. The solids are separated from the solvents byrotoevaporation, rinsed in Buchner funnel with water (2, 1 literportions) and dried in a vacuum oven.

Preparation ofpoly(caprolactone)-N-bis-[L-leucine]-1,3-diester-2-propanone-monotosylate

The poly(caprolactone) polymer from Example 3 (50 gm, 0.043 mole), thedi-p-toluenesulfonic acid salt ofbis-[L-leucine]-1,3-diester-2-propanone (28.38 gm, 0.043 mole),triethylamine (4.35 gm gm, 0.043 mole), and tetrahydrofuran (THF) (200ml) can be added to a 500 ml, 3-necked flask equipped with argon purgeand mechanical stirrer. After dissolution, DCC (8.87 gm, 0.043 mole) canbe added and the solution stirred overnight at ambient temperature. Thesolution can be filtered to remove the dicyclohexylurea formed andslowly added to methanol (1000 ml) with stirring to precipitate thepolymer. The polymer can be redissolved in chloroform (200 ml),precipitated in isopropyl alcohol (1000 ml), and dried under a vacuum ofabout 1 torr at about 40° C. for about 48 hours.

Preparation ofco-poly[N,N-adipoyl-bis-[L-leucine]-1,3-diester-2-propanone-polycaprolactone]

Poly(caprolactone)-N-bis-[L-leucine]-1,3-diester-2-propanone-monotosylate(52.6 gm, 0.0323 mole), triethylamine (10.79 gm, 0.107 mole), andanhydrous 2-butanone (125 ml) can be added to a 500 ml, 3-necked flaskequipped with mechanical stirrer, argon inlet, 50 ml addition funnel,and ice bath. After dissolution, a solution of adipoyl chloride (5.91gm, 0.0323 mole) in anhydrous 2-butanone (25 ml) can be added withstirring over 30 minutes while maintaining the reaction at 0° C. Thereaction can be allowed to warm to room temperature and stirred for 4more hours. The solution can be added to a deionized water (1000 ml)with stirring to precipitate the polymer. The polymer can be redissolvedin THF (200 ml) and reprecipitated in deionized water (1000 ml) withstirring. The polymer can be redissolved in chloroform (500 ml) andfiltered through a dry disc apparatus (Horizon Technologies, Atkinson,N.H.) to remove water. The solution can be concentrated by rotaryevaporation, poured into Teflon trays, and dried at about 40° C. under avacuum of about 1 torr for about 48 hours.

Method of preparing conjugate of estradiol and3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane (DETOSU)

Dry THF (40 ml) can be combined with DETOSU (5 gm, 0.0236 mole) and sixdrops of 1% p-toluenesulfonic acid in THF in a 100 ml flask. A solutionof estradiol (6.42 gm. 0.0236 mole) in THF (20 ml) can be slowly addedwith stirring for over an hour. The estradiol-DETOSU conjugate can beisolated by rotary evaporation.

Method of preparing the polymer of formula (XXII),co-poly[O,N-adipoyl-polycaprolactone-bis-[L-leucine]-1,3-propylenediester-2-DETOSU-Estradiol]

Co-poly[N,N-adipoyl-bis-[L-leucine]-1,3-diester-2-propanone-polycaprolactone](27.09 gm), dry THF (250 ml), sodium cyanoborohydride (1.05 gm, 0.0167mole), and p-toluenesulfonic acid (6 drops of a 1% solution) in THF canbe added to a 500 ml flask. The mixture can be stirred for two hours atambient temperature, poured into chloroform (500 ml), and extracted with3 portions of aqueous sodium bicarbonate (250 ml, 1M portions).Chloroform can be removed by rotary evaporation, and the remainingsolvent can be removed by drying overnight in a vacuum oven at ambienttemperature. The polymer (22.25 gm), dry THF (250 ml), and theestradiol-DETOSU conjugate (6.64 gm, 0.0137 mole) can be added to a 500ml flask and stirred at room temperature for two hours. The polymer canbe precipitated by slow addition into hexane/ethyl acetate (2 liters,50/50) with stirring to yield the polymer of formula (XXII).

Example 6 Preparation of a PHA-Lycosaminoglycan Copolymer Using anAldehyde-Derivatized Glycosaminoglycan such as the Heparin Shown inFormula (XXIII)

An aldehyde functional heparin obtained by periodate oxidation, or byoxidation with nitrous acid can be obtained from Celsus, Inc.,Cincinnati, Ohio. An ABA block copolymer with heparin endblocks can beprepared starting with a di-amino-functional PHA. Thedi-amino-functional poly(D,L-lactide) from Example 1 (5 gm, 0.00396mole), 90/10 dimethylformamide/water (250 ml), and aldehyde-heparin(0.0087 aldehyde molar equiv.) can be added to a 500 ml flask equippedwith magnetic stirrer and oil bath. After dissolution at 40° C., sodiumcyanoborohydride (2.73 gm, 0.044 mole) can be added, and the solutioncan be stirred at 40° C. for 48 hours. After cooling, the polymer can beprecipitated by addition to methanol (1000 ml). After isolation byfiltration, the polymer can be dried at about 40° under a vacuum ofabout 1 torr for about 48 hours.

An AB block heparin-PHA copolymer can be made similarly. Using thehydroxyl and carboxyl functional poly(caprolactone) from Example 2, thecarboxyl endgroup can be coupled with adipic dihydrazide using DCC. Theresulting hydrazido functional PHA can then be coupled to aldehydefunctional heparin via reductive amination.

The poly(caprolactone) from Example 2 (2.5 gm, 0.0021 mole), adipicdihydrazide (0.828 gm, 0.00476 mole), and THF (25 ml) can be added to a50 ml flask equipped with magnetic stirrer and oil bath. Afterdissolution, DCC (0.491 gm, 0.00238 mole) can be added, and the solutioncan be stirred at ambient temperature overnight. After filtration toremove the dicyclohexylurea, the solution can be slowly added tomethanol (250 ml) with stirring. The polymer can be isolated byfiltration and dried at about 40° under a vacuum of about 1 torr forabout 12 hours.

A benzalkonium salt of an aldehyde-functional heparin can be made bydissolving aldehyde-functional heparin in deionized water and adding astoichiometric amount of benzalkonium chloride per the sodium content ofthe heparin sodium. The benzalkonium heparin precipitates from solution.

Adipic hydrazide functional poly(caprolactone) (2 gm, 0.00152 mole), THF(100 ml), and aldehyde-heparin (0.00152 aldehyde molar equiv.) can beadded to a 250 ml flask equipped with a magnetic stirrer and oil bath.After dissolution at 40° C., sodium cyanoborohydride (0.472 gm, 0.0076mole) can be added, and the solution can be stirred at 40° C. for 48hours. After cooling, the polymer can be precipitated by addition todeionized water (1000 ml). After isolation by filtration, the polymercan be dried at about 40° under a vacuum of about 1 torr for about 48hours.

Example 7 Preparation of a PHA of the type of formula (XV),co-poly-{[N,N′-sebacoyl-bis-1,6-hexylenecarbamate-poly(D,L-lactide)-1,6-hexylenediester]₆₇-[N,N′-sebacoyl-L-lysinebenzyl ester]₃₃}

This preparation uses the di-amino-terminated poly(D,L-lactide) fromExample 1, a L-lysine benzyl ester ditosylate, and di-p-nitrophenylsebacinate. The amino-terminated poly(D,L-lactide) from Example 1 (25gm, 0.0198 mole), the di-p-toluenesulfonic acid salt of L-lysine benzylester (5.69 gm, 0.0098 mole), di-p-nitrophenyl sebacinate (13.2 gm,0.0296 mole), dry triethylamine (3.0 ml, 0.0216 mole), and anhydrousdimethylformamide (50 ml) can be added to a 3-necked, 500 ml flaskequipped with mechanical stirrer, argon inlet and oil bath. The mixturecan be stirred and heated at 80 C for 12 hours. The mixture can then becooled to room temperature, diluted with additional dimethyformamide(250 ml), and added dropwise with stirring to 1% aqueous sodiumcarbonate (1750 ml). The polymer can be isolated by filtration,redissolved in THF (250 ml) and precipitated by addition to deionizedwater (1750 ml). After isolation by filtration, the polymer can be driedat about 40° under a vacuum of about 1 torr for about 48 hours to yielda polymer of formula (XV) with a benzyl ester protected lysine.Subsequent hydrogenolysis of the benzyl ester will liberate the lysinecarboxyl and allow conjugation of biobeneficial moieties.

Example 8 Method of Preparing a PHA-PEG Conjugate with anAmino-Terminated PHA

An amino-terminated PHA can be coupled to PEG by aldehyde coupling/iminereduction, carbodiimide coupling of a carboxyl terminated PEG, andmaleimide coupling of a PEG-maleimide to an amino-terminated PHA.

A PHA (50 g) can be dissolved in anhydrous DMAC (230 g) in the couplingof PEG to amino-terminated PHA. A PEG-butyraldehyde (MW 1000-50,000, 7.5g) can be combined with sodium cyanoborohydride (1.0 g) and stirredovernight at room temperature under nitrogen. The polymer can beprecipitated by addition of the solution with stirring in methanol,redissolved in DMAC, reprecipitated in water, and dried under vacuum.

An amino-terminated PHA can be conjugated to PEG by carbodiimidecoupling of a carboxyl terminated PEG using DCC/NHS coupling. Anamino-terminated PHA (50 g) can be added to anhydrous THF (116 g; 1-35%w/w). Anhydrous THF (116 g) and carboxyl-terminated PEG (10 kD, 7.0 g,0.7 mmol), DCC (0.15 g; 7.1 mmol) (DCC) can be added to a reactorcontaining N-hydroxysuccinimide (0.10 g/8 mmol) (NHS) to form a mixture.The mixture can be stirred under nitrogen for 2 hours at roomtemperature, and the amino-terminated PHA solution can be added to themixture in a dropwise manner, stirred overnight at room temperature, andadded dropwise to methanol to form a PHA-PEG precipitate. Theprecipitate can be filtered and dried under vacuum.

Example 9

A medical article with two layers of coating can be fabricated tocomprise everolimus by preparing a first composition and a secondcomposition, wherein the first composition can be an agent layercomprising a matrix of a PHA and agent, and the second composition canbe a PHA topcoat layer. The first composition can be prepared by mixinga functionalized PHA with the everolimus in absolute ethanol, sprayedonto a surface of a bare 12 mm VISION™ stent (Guidant Corp.) (“examplestent”) and dried to form a coating. An example coating techniquecomprises spray-coating with a 0.014 fan nozzle, a feed pressure ofabout 0.2 atm and an atomization pressure of about 1.3 atm; applyingabout 20 μg of wet coating per pass; drying the coating at about 50° C.for about 10 seconds between passes and baking the coating at about 50°C. for about 1 hour after the final pass to form a dry agent layer. Asecond composition can be prepared by mixing the PHA in absolute ethanoland applying the PHA using the example coating technique.

Example 10

A medical article with three layers of coating can be fabricated tocomprise everolimus by preparing a first composition, a secondcomposition and a third composition. The first composition can be aprimer layer of a PHA. The second composition can be a pure agent layer,and the third composition can be a topcoat layer of a PHA. The firstcomposition can be prepared by mixing about 2% (w/w) of the PHA inabsolute ethanol and can be applied onto the surface of the examplestent using the example coating technique to form a dry primer layer.The dry primer layer can contain about 100 μg of the PHA. The secondcomposition can be prepared by mixing about 2% (w/w) everolimus inabsolute ethanol and applying the mixture to the primer layer using acoating technique to form a pure agent layer comprising everolimus. Thethird composition can be prepared by mixing about 2% (w/w) of the PHA inabsolute ethanol and applying the mixture using a coating technique toform a topcoat layer comprising the PHA.

While particular embodiments of the present invention have been shownand described, those skilled in the art will note that variations andmodifications can be made to the present invention without departingfrom the spirit and scope of the teachings. A multitude of chemicalstructures, polymers, agents and methods have been taught herein. One ofskill in the art is to appreciate that such teachings are provided byway of example only and are not intended to limit the scope of theinvention. For example, the chemical structures taught herein are meantto cover all stereoisomerism possible for each chemical structurerepresented rather than to depict any particular stereoisomerism, unlessotherwise specified.

1. A composition comprising a polymer represented by a formula:

wherein the ratio of A:B is less than, greater than, or equal to one; Acomprises

B comprises a biobeneficial agent comprising a poly(ester amide)

where R₁ is selected from a group consisting of alkylenes, alkanoates,alkyl alkanoates, diesters, acylals, diacids, saturated fatty acids,glycerides, and combinations thereof; R₂ is selected from a groupconsisting of substituted, unsubstituted, hetero-, straight-chained,branched, cyclic, saturated and unsaturated aliphatic radicals; andsubstituted, unsubstituted, and hetero-aromatic radicals; R₃ is selectedfrom a group consisting of hydrogen; substituted, unsubstituted,hetero-, straight-chained, branched, cyclic, saturated and unsaturatedaliphatic radicals; and substituted, unsubstituted, and hetero-aromaticradicals; R₄ is selected from a group consisting of substituted,unsubstituted, hetero-, straight-chained, branched, cyclic, saturatedand unsaturated aliphatic radicals; and substituted, unsubstituted, andhetero-aromatic radicals; R₆ is optional and is selected from a groupconsisting of substituted, unsubstituted, hetero-, straight-chained,branched, cyclic, saturated and unsaturated aliphatic radicals; andsubstituted, unsubstituted, and hetero-aromatic radicals; R₈ is selectedfrom a group consisting of substituted, unsubstituted, hetero-,straight-chained, branched, cyclic, saturated and unsaturated aliphaticradicals; and substituted, unsubstituted, and hetero-aromatic radicals;R₁₁ through R₁₄ are independently selected from a group consisting ofhydrogen; substituted, unsubstituted, hetero-, straight-chained,branched, cyclic, saturated and unsaturated aliphatic radicals; andsubstituted, unsubstituted, and hetero-, aromatic radicals; L₁ is alinkage connecting A to B; X is an agent; L₂ is a linkage connecting Xto said polymer; k is an integer; m is an integer from about 1 to about40; and n, p, and z are integers not equal to zero, and wherein theagent comprises a component selected from a group consisting ofphosphorylcholine, poly(N-vinyl pyrrolidone), poly(acrylamide methylpropane sulfonic acid), poly(styrene sulfonate), polysaccharides,poly(ester amides), non-thrombotics, antimicrobials, and combinationsthereof.
 2. The composition of claim 1, wherein the polysaccharidecomprises a component selected from a group consisting ofcarboxymethylcellulose, sulfonated dextran, sulfated dextran, dermatansulfate, chondroitin sulfate, hyaluronic acid, heparin, hirudin, and anyderivatives, analogs, homologues, congeners, salts, copolymers andcombinations thereof.
 3. The composition of claim 1, wherein the agentcomprises a component selected from a group consisting of a free radicalscavenger, a nitric oxide donor, rapamycin, methyl rapamycin,everolimus, 42-Epi-(tetrazoylyl)rapamycin (ABT-578), tacrolimus,paclitaxel, docetaxel, estradiol, clobetasol, idoxifen, tazarotene andany prodrugs, metabolites, analogs, homologues, congeners, and anyderivatives, salts and combinations thereof.
 4. The composition of claim3, wherein the free radical scavenger comprises a component selectedfrom a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, freeradical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical;4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical;2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, freeradical; 16-doxyl-stearic acid, free radical; superoxide dismutasemimic; and, any analogs, homologues, congeners, derivatives, salts andcombinations thereof.
 5. The composition of claim 3, wherein the freeradical scavenger comprises a component selected from a group consistingof TEMPO and any analogs, homologues, congeners, derivatives, salts orcombinations thereof.
 6. The composition of claim 3, wherein the nitricoxide donor comprises a component selected from the group consisting ofS-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitricoxide synthase, diazenium diolates and any analogs, homologues,congeners, derivatives, salts and combinations thereof.
 7. Thecomposition of claim 1 further comprising an additional agent that iscombined with the composition.
 8. The composition of claim 7, whereinthe additional agent comprises an essential oil.
 9. The composition ofclaim 8, wherein the essential oil comprises garlic oil.
 10. Thecomposition of claim 7, wherein the additional agent comprises acomponent selected from a group consisting of castor oil, fish oil,ethanol, xylene, dimethyl formamide, glycerol, and combinations thereof.11. The composition of claim 1, wherein L₁ or L₂ comprises a componentselected from a group consisting of amides, esters, anhydrides,orthoesters, all-aromatic carbonates, and combinations thereof.